Compounds, Compositions and Methods

ABSTRACT

The present disclosure relates generally to compounds and compositions, and their use as kinase inhibitors.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a divisional of U.S. application Ser. No.16/130,817, filed Sep. 13, 2018, which is a divisional of Ser. No.15/721,470, filed Sep. 29, 2017, now U.S. Pat. No. 10,131,676, which isa divisional of U.S. application Ser. No. 15/424,216, filed Feb. 3,2017, now U.S. Pat. No. 9,815,850, which claims priority under 35 U.S.C.119(e) of U.S. Provisional Application Nos. 62/292,202, filed Feb. 5,2016, 62/341,019, filed May 24, 2016, 62/363,775, filed Jul. 18, 2016,62/385,217, filed Sep. 8, 2016, and 62/417,219, filed Nov. 3, 2016. Theentire contents of these applications are incorporated by reference intothis application.

FIELD

The present disclosure relates generally to inhibitors of kinase,therapeutic methods of use, and manufacture thereof.

BACKGROUND

Although inflammation can be a protective mechanism in response toharmful stimuli such as invasion of pathogens and tissue damages,chronic inflammation is an important underlying factor in many humandiseases such as neurodegeneration, rheumatoid arthritis, autoimmune andinflammatory diseases, and cancer. Similarly, the activation of celldeath pathways, such as necrosis and apoptosis which are useful ineliminating infected or damaged cells, is also an important underlyingmechanism for human diseases, including acute and chronicneurodegenerative diseases.

Receptor-interacting protein kinase 1 is a key regulator ofinflammation, apoptosis and necroptosis. Receptor-interacting proteinkinase 1 has an important role in modulating inflammatory responsesmediated by nuclear-factor kappa-light chain enhancer of activated Bcells (NF-κB). More recent research has shown that its kinase activitycontrols necroptosis, a form of necrotic cell death, which wastraditionally thought to be passive and unregulated, and ischaracterized by a unique morphology. Further, receptor-interactingprotein kinase 1 is part of a pro-apoptotic complex indicating itsactivity in regulating apoptosis.

The receptor-interacting protein kinase 1 is subject to complex andintricate regulatory mechanisms, including ubiquitylation,deubiquitylation and phosphorylation. These regulatory eventscollectively determine whether a cell will survive and activate aninflammatory response or die through apoptosis or necroptosis.Dysregulation of receptor-interacting protein kinase 1 signaling canlead to excessive inflammation or cell death, and conversely, researchhas shown that inhibition of receptor-interacting protein kinase 1 canbe effective therapies for diseases involving inflammation or celldeath.

DESCRIPTION

Provided herein are compounds that are useful as inhibitors ofreceptor-interacting protein kinase 1. The disclosure also providescompositions, including pharmaceutical compositions, kits that includethe compounds, and methods of using (or administering) and making thecompounds. The disclosure further provides compounds or compositionsthereof for use in a method of treating a disease, disorder, orcondition that is mediated by receptor-interacting protein kinase 1.Moreover, the disclosure provides uses of the compounds or compositionsthereof in the manufacture of a medicament for the treatment of adisease, disorder or condition that is mediated by (or mediated, atleast in part, by) receptor-interacting protein kinase 1.

In certain embodiments, provided is a compound of Formula I. In certainembodiments, provided is a compound of Formula IIc. In certainembodiments, provided is a compound of Formula IIe. In certainembodiments, provided is a compound of Formula IIf. In certainembodiments, provided is a compound of Formula V. In certainembodiments, provided is a compound of Formula Va. In certainembodiments, provided is a compound of Formula VI. In certainembodiments, provided is a compound as in Table 1, or a pharmaceuticallyacceptable salt, prodrug, tautomer, stereoisomer or mixture ofstereoisomers thereof. In certain embodiments, provided is a compound asin Table 2, or a pharmaceutically acceptable salt, prodrug, tautomer,stereoisomer or mixture of stereoisomers thereof. In certainembodiments, provided is a compound as in Table 3, or a pharmaceuticallyacceptable salt, prodrug, tautomer, stereoisomer or mixture ofstereoisomers thereof. In certain embodiments, provided is a compound asin Table 4, or a pharmaceutically acceptable salt, prodrug, tautomer,stereoisomer or mixture of stereoisomers thereof.

Provided herein is a pharmaceutical composition comprising a compound,including those of any Formula described herein, and an excipient.

Provided herein are compounds and compositions for use in medicine. Incertain embodiments, the compounds and compositions are for use in thetreatment of a receptor-interacting protein kinase 1-mediated disease ordisorder.

Provided herein is a method of treating a receptor-interacting proteinkinase 1-mediated disease or disorder comprising administering atherapeutically effective amount of a compound or pharmaceuticalcomposition disclosed herein to a subject in need thereof.

In certain embodiments, the disease or disorder is inflammatory boweldisease, Crohn's disease, ulcerative colitis, psoriasis, retinaldetachment, retinitis pigmentosa, macular degeneration, pancreatitis,atopic dermatitis, rheumatoid arthritis, spondyloarthritis, gout, SoJIA,systemic lupus erythematosus, Sjogren's syndrome, systemic scleroderma,anti-phospholipid syndrome, vasculitis, osteoarthritis, non-alcoholsteatohepatitis, alcohol steatohepatitis, autoimmune hepatitis,autoimmune hepatobiliary diseases, primary sclerosing cholangitis,nephritis, Celiac disease, autoimmune ITP, transplant rejection,ischemia reperfusion injury of solid organs, sepsis, systemicinflammatory response syndrome, cerebrovascular accident, myocardialinfarction, Huntington's disease, Alzheimer's disease, Parkinson'sdisease, allergic diseases, asthma, atopic dermatitis, multiplesclerosis, type I diabetes, Wegener's granulomatosis, pulmonarysarcoidosis, Behget's disease, interleukin-1 converting enzymeassociated fever syndrome, chronic obstructive pulmonary disease, tumornecrosis factor receptor-associated periodic syndrome, or peridontitis.In certain embodiments, the disease or disorder is trauma, ischemia,stroke, cardiac infarction, infection, lysomal storage disease,Gaucher's disease, Krabbe disease, Niemann-Pick disease, sepsis,Parkinson's disease, Alzheimer's disease, amyotrophic lateral sclerosis(ALS/Lou Gehrig's Disease), Huntington's disease, HIV-associateddementia, retinal degenerative disease, glaucoma, age-related maculardegeneration, rheumatoid arthritis, psoriasis, psoriatic arthritis orinflammatory bowel disease. In certain embodiments, the disease ordisorder is Alzheimer's disease, ALS, Friedreich's ataxia, Huntington'sdisease, Lewy body disease, Parkinson's disease, or spinal muscularatrophy. In certain embodiments, the disease or disorder is braininjury, spinal cord injury, dementia, stroke, Alzheimer's disease, ALS,Parkinson's disease, Huntington's disease, multiple sclerosis, diabeticneuropathy, polyglutamine (polyQ) diseases, stroke, Fahr disease,Menke's disease, Wilson's disease, cerebral ischemia, or a priondisorder.

1. Definitions

The following description sets forth exemplary embodiments of thepresent technology. It should be recognized, however, that suchdescription is not intended as a limitation on the scope of the presentdisclosure but is instead provided as a description of exemplaryembodiments.

As used in the present specification, the following words, phrases andsymbols are generally intended to have the meanings as set forth below,except to the extent that the context in which they are used indicatesotherwise.

A dash (“-”) that is not between two letters or symbols is used toindicate a point of attachment for a substituent. For example, —C(O)NH₂is attached through the carbon atom. A dash at the front or end of achemical group is a matter of convenience; chemical groups may bedepicted with or without one or more dashes without losing theirordinary meaning. A wavy line drawn through a line in a structureindicates a point of attachment of a group. Unless chemically orstructurally required, no directionality or stereochemistry is indicatedor implied by the order in which a chemical group is written or named.

The prefix “C_(u-v)” indicates that the following group has from u to vcarbon atoms. For example, “C₁₋₆ alkyl” indicates that the alkyl grouphas from 1 to 6 carbon atoms.

Reference to “about” a value or parameter herein includes (anddescribes) embodiments that are directed to that value or parameter perse. In certain embodiments, the term “about” includes the indicatedamount±10%. In certain embodiments, the term “about” includes theindicated amount±5%. In certain embodiments, the term “about” includesthe indicated amount±1%. Also, to the term “about X” includesdescription of “X”. Also, the singular forms “a” and “the” includeplural references unless the context clearly dictates otherwise. Thus,e.g., reference to “the compound” includes a plurality of such compoundsand reference to “the assay” includes reference to one or more assaysand equivalents thereof known to those skilled in the art.

“Alkyl” refers to an unbranched or branched saturated hydrocarbon chain.As used herein, alkyl has 1 to 20 carbon atoms (i.e., C₁₋₂₀ alkyl), 1 to8 carbon atoms (i.e., C₁₋₈ alkyl), 1 to 6 carbon atoms (i.e., C₁₋₆alkyl), or 1 to 4 carbon atoms (i.e., C₁₋₄ alkyl). In certainembodiments, alkyl has 1 to 12 carbon atoms (i.e., C₁₋₁₂ alkyl).Examples of alkyl groups include methyl, ethyl, propyl, isopropyl,n-butyl, sec-butyl, iso-butyl, tert-butyl, pentyl, 2-pentyl, isopentyl,neopentyl, hexyl, 2-hexyl, 3-hexyl, and 3-methylpentyl. When an alkylresidue having a specific number of carbons is named by chemical name oridentified by molecular formula, all positional isomers having thatnumber of carbons may be encompassed; thus, for example, “butyl”includes n-butyl (i.e. —(CH₂)₃CH₃), sec-butyl (i.e. —CH(CH₃)CH₂CH₃),isobutyl (i.e. —CH₂CH(CH₃)₂) and tert-butyl (i.e. —C(CH₃)₃); and“propyl” includes n-propyl (i.e. —(CH₂)₂CH₃) and isopropyl (i.e.—CH(CH₃)₂).

“Alkenyl” refers to an alkyl group containing at least one carbon-carbondouble bond and having from 2 to 20 carbon atoms (i.e., C₂₋₂₀ alkenyl),2 to 8 carbon atoms (i.e., C₂₋₈ alkenyl), 2 to 6 carbon atoms (i.e.,C₂₋₆ alkenyl), or 2 to 4 carbon atoms (i.e., C₂₋₄ alkenyl). Examples ofalkenyl groups include ethenyl, propenyl, butadienyl (including1,2-butadienyl and 1,3-butadienyl).

“Alkynyl” refers to an alkyl group containing at least one carbon-carbontriple bond and having from 2 to 20 carbon atoms (i.e., C₂₋₂₀ alkynyl),2 to 8 carbon atoms (i.e., C₂₋₈ alkynyl), 2 to 6 carbon atoms (i.e.,C₂₋₆ alkynyl), or 2 to 4 carbon atoms (i.e., C₂₋₄ alkynyl). The term“alkynyl” also includes those groups having one triple bond and onedouble bond.

“Alkoxy” refers to the group “alkyl-O—”. Examples of alkoxy groupsinclude methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, tert-butoxy,sec-butoxy, n-pentoxy, n-hexoxy, and 1,2-dimethylbutoxy.

“Alkylthio” refers to the group “alkyl-S—”.

“Acyl” refers to a group —C(O)R, wherein R is hydrogen, alkyl, alkenyl,alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl;each of which may be optionally substituted, as defined herein. Examplesof acyl include formyl, acetyl, cyclcohexylcarbonyl,cyclohexylmethyl-carbonyl, and benzoyl.

“Amido” refers to both a “C-amido” group which refers to the group—C(O)NR^(y)R^(z) and an “N-amido” group which refers to the group—NR^(y)C(O)R^(z), wherein R and R are independently selected from thegroup consisting of hydrogen, alkyl, aryl, haloalkyl, or heteroaryl;each of which may be optionally substituted.

“Amino” refers to the group —NR^(y)R^(z) wherein R and R^(z) areindependently selected from the group consisting of hydrogen, alkyl,cycloalkyl, haloalkyl, aryl, or heteroaryl; each of which may beoptionally substituted.

“Amidino” refers to —C(NH)(NH₂). In certain embodiments, “Amidino”refers to —C(NR)(NR₂), wherein each R is independently hydrogen, alkyl,alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl orheteroaryl; each of which may be optionally substituted, as definedherein.

“Aryl” refers to an aromatic carbocyclic group having a single ring(e.g. monocyclic) or multiple rings (e.g. bicyclic or tricyclic)including fused systems. As used herein, aryl has 6 to 20 ring carbonatoms (i.e., C₆₋₂₀ aryl), 6 to 12 carbon ring atoms (i.e., C₆₋₁₂ aryl),or 6 to 10 carbon ring atoms (i.e., C₆₋₁₀ aryl). In certain embodiments,aryl has 6 to 18 carbon ring atoms (i.e., C₆₋₁₈ aryl). Examples of arylgroups include phenyl, naphthyl, fluorenyl, and anthryl. Aryl, however,does not encompass or overlap in any way with heteroaryl defined below.If one or more aryl groups are fused with a heteroaryl, the resultingring system is heteroaryl. If one or more aryl groups are fused with aheterocyclyl, the resulting ring system is heterocyclyl.

“Azido” refers to —N₃.

“Arylalkyl” or “Aralkyl” refers to the group “aryl-alkyl-”.

“Carbamoyl” refers to both an “O-carbamoyl” group which refers to thegroup —O—C(O)NR^(y)R^(z) and an “N-carbamoyl” group which refers to thegroup —NR^(y)C(O)OR^(z), wherein R and R are independently selected fromthe group consisting of hydrogen, alkyl, aryl, haloalkyl, or heteroaryl;each of which may be optionally substituted.

“Carboxyl” refers to —C(O)OH.

“Carboxyl ester” or “ester” refer to both —OC(O)R and —C(O)OR, wherein Ris hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl,heteroalkyl, or heteroaryl; each of which may be optionally substituted,as defined herein.

“Cyano” or “carbonitrile” refers to the group —CN.

“Cycloalkyl” refers to a saturated or partially unsaturated cyclic alkylgroup having a single ring or multiple rings including fused, bridged,and spiro ring systems. The term “cycloalkyl” includes cycloalkenylgroups (i.e. the cyclic group having at least one double bond). As usedherein, cycloalkyl has from 3 to 20 ring carbon atoms (i.e., C₃₋₂₀cycloalkyl), 3 to 12 ring carbon atoms (i.e., C₃₋₁₂ cycloalkyl), 3 to 10ring carbon atoms (i.e., C₃₋₁₀ cycloalkyl), 3 to 8 ring carbon atoms(i.e., C₃₋₈ cycloalkyl), or 3 to 6 ring carbon atoms (i.e., C₃₋₆cycloalkyl). In certain embodiments, cycloalkyl has from 3 to 15 ringcarbon atoms (i.e., C₃₋₁₅ cycloalkyl). Examples of cycloalkyl groupsinclude cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. Further,the term cycloalkyl is intended to encompass any non-aromatic ring whichmay be fused to an aryl ring, regardless of the attachment to theremainder of the molecule.

In certain embodiments, cycloalkyl also includes “spiro cycloalkyl” whenthere are two positions for substitution on the same carbon atom.Monocyclic radicals include, for example, cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl. Polycyclic radicalsinclude, for example, adamantyl, norbornyl, decalinyl,7,7-dimethyl-bicyclo[2.2.1]heptanyl and the like.

“Guanidino” refers to —NHC(NH)(NH₂). In certain embodiments, “guanidino”refers to —NRC(NR)(NR₂), wherein each R is hydrogen, alkyl, alkenyl,alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl or heteroaryl; eachof which may be optionally substituted, as defined herein.

“Cycloalkylalkyl” refers to the group “cycloalkyl-alkyl-”.

“Hydrazino” refers to —NHNH₂.

“Imino” refers to a group —C(NR)R, wherein each R is independentlyhydrogen alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl,heteroalkyl, or heteroaryl; each of which may be optionally substituted,as defined herein.

“Imido” refers to a group —C(O)NRC(O)R, wherein each R is independentlyhydrogen alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl,heteroalkyl, or heteroaryl; each of which may be optionally substituted,as defined herein.

“Halogen” or “halo” includes fluoro, chloro, bromo, and iodo.

“Haloalkyl” refers to an unbranched or branched alkyl group as definedabove, wherein one or more hydrogen atoms are replaced by a halogen. Forexample, where a residue is substituted with more than one halogen, itmay be referred to by using a prefix corresponding to the number ofhalogen moieties attached. Dihaloalkyl and trihaloalkyl refer to alkylsubstituted with two (“di”) or three (“tri”) halo groups, which may be,but are not necessarily, the same halogen. Examples of haloalkyl includedifluoromethyl (—CHF₂) and trifluoromethyl (—CF₃). In certainembodiments, examples of haloalkyl include difluoromethyl,trifluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl,1,2-difluoroethyl, 3-bromo-2-fluoropropyl, 1,2-dibromoethyl and thelike.

“Haloalkoxy” refers to an alkoxy group as defined above, wherein one ormore hydrogen atoms are replaced by a halogen.

“Hydroxyalkyl” refers to an alkyl group as defined above, wherein one ormore hydrogen atoms are replaced by a hydroxy group.

“Heteroalkyl” refers to an alkyl group in which one or more of thecarbon atoms (and any associated hydrogen atoms) are each independentlyreplaced with the same or different heteroatomic group. The term“heteroalkyl” includes unbranched or branched saturated chain havingcarbon and heteroatoms. By way of example, 1, 2 or 3 carbon atoms may beindependently replaced with the same or different heteroatomic group.Heteroatomic groups include, but are not limited to, —NR—, —O—, —S—,—S(O)—, —S(O)₂—, and the like, where R is H, alkyl, alkenyl, alkynyl,aryl, cycloalkyl, heteroalkyl, heteroaryl or heterocyclyl, each of whichmay be optionally substituted. Examples of heteroalkyl groups include—OCH₃, —CH₂OCH₃, —SCH₃, —CH₂SCH₃, —NRCH₃, and —CH₂NRCH₃, where R ishydrogen, alkyl, aryl, arylalkyl, heteroalkyl, or heteroaryl, each ofwhich may be optionally substituted. In certain embodiments, examples ofheteroalkyl groups include —CH₂CH₃, —CH₂SCH₃, and —CH₂NRCH₃, where R ishydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl,heteroalkyl, or heteroaryl; each of which may be optionally substituted,as defined herein. As used herein, heteroalkyl includes 1 to 10 carbonatoms, 1 to 8 carbon atoms, or 1 to 4 carbon atoms; and 1 to 3heteroatoms, 1 to 2 heteroatoms, or 1 heteroatom. In certainembodiments, the term “heteroalkyl” requires that the point ofattachment to the remainder of the molecule is through a carbon atom.

“Heteroaryl” refers to an aromatic group having a single ring, multiplerings, or multiple fused rings, with one or more ring heteroatomsindependently selected from nitrogen, oxygen, and sulfur. As usedherein, heteroaryl includes 1 to 20 ring carbon atoms (i.e., C₁₋₂₀heteroaryl), 3 to 12 ring carbon atoms (i.e., C₃₋₁₂ heteroaryl), or 3 to8 carbon ring atoms (i.e., C₃₋₈ heteroaryl); and 1 to 5 heteroatoms, 1to 4 heteroatoms, 1 to 3 ring heteroatoms, 1 to 2 ring heteroatoms, or 1ring heteroatom independently selected from nitrogen, oxygen, andsulfur. In certain embodiments, the term “heteroaryl” refers to a 5-14membered ring system. In certain embodiments, heteroaryl includes 1 to13 ring carbon atoms (i.e., C₃₋₁₂ heteroaryl). In certain embodiments,heteroaryl includes 1 to 6 heteroatoms. Examples of heteroaryl groupsinclude pyrimidinyl, purinyl, pyridyl, pyridazinyl, benzothiazolyl, andpyrazolyl. Examples of the fused-heteroaryl rings include, but are notlimited to, benzo[d]thiazolyl, quinolinyl, isoquinolinyl,benzo[b]thiophenyl, indazolyl, benzo[d]imidazolyl,pyrazolo[1,5-a]pyridinyl, and imidazo[1,5-a]pyridinyl, where theheteroaryl can be bound via either ring of the fused system. In certainembodiments, examples of heteroaryl groups include azepinyl, acridinyl,benzimidazolyl, benzothiazolyl, benzindolyl, benzodioxolyl,benzofuranyl, benzooxazolyl, benzothiazolyl, benzothiadiazolyl,benzo[b][1,4]dioxepinyl, 1,4-benzodioxanyl, benzonaphthofuranyl,benzoxazolyl, benzodioxolyl, benzodioxinyl, benzopyranyl,benzopyranonyl, benzofuranyl, benzofuranonyl, benzothienyl(benzothiophenyl), benzotriazolyl, benzo[4,6]imidazo[1,2-a]pyridinyl,carbazolyl, cinnolinyl, dibenzofuranyl, dibenzothiophenyl, furanyl,furanonyl, isothiazolyl, imidazolyl, indazolyl, indolyl, indazolyl,isoindolyl, indolinyl, isoindolinyl, isoquinolyl, indolizinyl,isoxazolyl, naphthyridinyl, oxadiazolyl, 2-oxoazepinyl, oxazolyl,oxiranyl, 1-oxidopyridinyl, 1-oxidopyrimidinyl, 1-oxidopyrazinyl,1-oxidopyridazinyl, 1-phenyl-1H-pyrrolyl, phenazinyl, phenothiazinyl,phenoxazinyl, phthalazinyl, pteridinyl, purinyl, pyrrolyl, pyrazolyl,pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, quinazolinyl,quinoxalinyl, quinolinyl, quinuclidinyl, isoquinolinyl,tetrahydroquinolinyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl,triazinyl and thiophenyl (i.e., thienyl). Any aromatic ring, having asingle or multiple fused rings, containing at least one heteroatom, isconsidered a heteroaryl regardless of the attachment to the remainder ofthe molecule (i.e., through any one of the fused rings). Heteroaryl doesnot encompass or overlap with aryl as defined above.

“Heteroarylalkyl” refers to the group “heteroaryl-alkyl-”.

“Heterocyclyl” refers to a saturated or unsaturated cyclic alkyl group,with one or more ring heteroatoms independently selected from nitrogen,oxygen and sulfur. The term “heterocyclyl” includes heterocycloalkenylgroups (i.e. the heterocyclyl group having at least one double bond),bridged-heterocyclyl groups, fused-heterocyclyl groups, andspiro-heterocyclyl groups. A heterocyclyl may be a single ring ormultiple rings wherein the multiple rings may be fused, bridged, orspiro. In certain embodiments, heterocyclyl may comprise one or more oxo(C═O) or N-oxide (N—O—) moieties. Any non-aromatic ring containing atleast one heteroatom is considered a heterocyclyl, regardless of theattachment (i.e., can be bound through a carbon atom or a heteroatom).Further, the term heterocyclyl is intended to encompass any non-aromaticring containing at least one heteroatom, which ring may be fused to anaryl or heteroaryl ring, regardless of the attachment to the remainderof the molecule. As used herein, heterocyclyl has 2 to 20 ring carbonatoms (i.e., C₂₋₂₀ heterocyclyl), 2 to 12 ring carbon atoms (i.e., C₂₋₁₂heterocyclyl), 2 to 10 ring carbon atoms (i.e., C₂₋₁₀ heterocyclyl), 2to 8 ring carbon atoms (i.e., C₂₋₈ heterocyclyl), 3 to 12 ring carbonatoms (i.e., C₃₋₁₂ heterocyclyl), 3 to 8 ring carbon atoms (i.e., C₃₋₈heterocyclyl), or 3 to 6 ring carbon atoms (i.e., C₃₋₆ heterocyclyl);having 1 to 5 ring heteroatoms, 1 to 4 ring heteroatoms, 1 to 3 ringheteroatoms, 1 to 2 ring heteroatoms, or 1 ring heteroatom independentlyselected from nitrogen, sulfur or oxygen. Examples of heterocyclylgroups include pyrrolidinyl, piperidinyl, piperazinyl, oxetanyl,dioxolanyl, azetidinyl, and morpholinyl. In certain embodiments,examples of heterocyclyl groups include dioxolanyl,thienyl[1,3]dithianyl, decahydroisoquinolyl, imidazolinyl,imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl,octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl,2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl,piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl,thiazolidinyl, tetrahydrofuryl, trithianyl, tetrahydropyranyl,thiomorpholinyl, thiamorpholinyl, 1-oxo-thiomorpholinyl and1,1-dioxo-thiomorpholinyl. Also used herein, the term“spiro-heterocyclyl” refers to a ring system in which a three- toten-membered heterocyclyl has one or more additional ring, wherein theone or more additional ring is three- to ten-membered cycloalkyl orthree- to ten-membered heterocyclyl, where a single atom of the one ormore additional ring is also an atom of the three- to ten-memberedheterocyclyl. Examples of the spiro-heterocyclyl rings include bicyclicand tricyclic ring systems, such as 2-oxa-7-azaspiro[3.5]nonanyl,2-oxa-6-azaspiro[3.4]octanyl, and 6-oxa-1-azaspiro[3.3]heptanyl.Examples of the fused-heterocyclyl rings include, but are not limitedto, 1,2,3,4-tetrahydroisoquinolinyl,4,5,6,7-tetrahydrothieno[2,3-c]pyridinyl, indolinyl, and isoindolinyl,where the heterocyclyl can be bound via either ring of the fused system.

“Hydroxy” or “hydroxyl” refers to the group —OH.

“Oxo” refers to the group (═O) or (O).

“Nitro” refers to the group —NO₂.

“Heterocyclylalkyl” refers to the group “heterocyclyl-alkyl-”.

“Oxime” refers to the group —CR(═NOH) wherein R is hydrogen, alkyl,alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl orheteroaryl; each of which may be optionally substituted, as definedherein.

“Sulfonyl” refers to the group —S(O)₂R, where R is alkyl, haloalkyl,heterocyclyl, cycloalkyl, heteroaryl, or aryl. Examples of sulfonyl aremethylsulfonyl, ethylsulfonyl, phenylsulfonyl, and toluenesulfonyl.

“Sulfinyl” refers to the group —S(O)R, where R is hydrogen, alkyl,alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl orheteroaryl; each of which may be optionally substituted, as definedherein. Examples of sulfinyl are methylsulfinyl, ethylsulfinyl,phenylsulfinyl and toluenesulfinyl.

“Sulfonamido” refers to the groups —SO₂NRR and —NRSO₂R, where each R isindependently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl,heterocyclyl, aryl, heteroalkyl or heteroaryl; each of which may beoptionally substituted, as defined herein.

“Alkylsulfonyl” refers to the group —S(O)₂R, where R is alkyl.

“Alkylsulfinyl” refers to the group —S(O)R, where R is alkyl.

“Thiocyanate” refers to the group —SCN.

“Thiol” refers to the group —SH.

“Thioxo” or “thione” refer to the group (═S) or (S).

In certain embodiments of any of the terms defined above, R and R areindependently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl,heterocyclyl, aryl, heteroalkyl or heteroaryl; each of which may beoptionally substituted, as defined herein.

In certain embodiments of any of the terms defined above, R is hydrogen,alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl orheteroaryl; each of which may be optionally substituted, as definedherein. Certain commonly used alternative chemical names may be used.For example, a divalent group such as a divalent “alkyl” group, adivalent “aryl” group, etc., may also be referred to as an “alkylene”group or an “alkylenyl” group, an “arylene” group or an “arylenyl”group, respectively. Also, unless indicated explicitly otherwise, wherecombinations of groups are referred to herein as one moiety, e.g.arylalkyl, the last mentioned group contains the atom by which themoiety is attached to the rest of the molecule.

The terms “optional” or “optionally” means that the subsequentlydescribed event or circumstance may or may not occur, and that thedescription includes instances where said event or circumstance occursand instances in which it does not. Also, the term “optionallysubstituted” refers to any one or more hydrogen atoms on the designatedatom or group may or may not be replaced by a moiety other thanhydrogen.

The term “substituted” means that any one or more hydrogen atoms on thedesignated atom or group is replaced with one or more substituents otherthan hydrogen, provided that the designated atom's normal valence is notexceeded. The one or more substituents include, but are not limited to,alkyl, alkenyl, alkynyl, alkoxy, acyl, amino, amido, amidino, aryl,azido, carbamoyl, carboxyl, carboxyl ester, cyano, guanidino, halo,haloalkyl, haloalkoxy, heteroalkyl, heteroaryl, heterocyclyl, hydroxy,hydrazino, imino, oxo, nitro, alkylsulfinyl, sulfonic acid,alkylsulfonyl, thiocyanate, thiol, thione, or combinations thereof.

In certain embodiments, the term “substituted” used herein means any ofthe above groups (i.e., alkyl, alkenyl, alkynyl, alkylene, alkoxy,haloalkyl, haloalkoxy, cycloalkyl, aryl, heterocyclyl, heteroaryl,and/or heteroalkyl) wherein at least one hydrogen atom is replaced by abond to a non-hydrogen atom such as, but not limited to alkyl, alkenyl,alkynyl, alkoxy, alkylthio, acyl, amido, amino, amidino, aryl, aralkyl,azido, carbamoyl, carboxyl, carboxyl ester, cyano, cycloalkyl,cycloalkylalkyl, guanadino, halo, haloalkyl, haloalkoxy, hydroxyalkyl,heteroalkyl, heteroaryl, heteroarylalkyl, heterocyclyl,heterocyclylalkyl, hydrazine, hydrazone, imino, imido, hydroxy, oxo,oxime, nitro, sulfonyl, sulfinyl, alkylsulfonyl, alkylsulfinyl,thiocyanate, sulfinic acid, sulfonic acid, sulfonamido, thiol, thioxo,N-oxide, or —Si(R¹⁰⁰)₃ wherein each R¹⁰⁰ is independently hydrogen,alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, aryl, heteroaryl orheterocyclyl.

In certain embodiments, the term “substituted” used herein means any ofthe above groups (i.e., alkyl, alkylene, alkoxy, haloalkoxy, aryl,cycloalkyl, haloalkyl, heterocyclyl, heteroaryl, hydroxyalkyl and/oralkoxyalkyl) wherein at least one hydrogen atom is replaced by a bond toa non-hydrogen atom such as, but not limited to: an alkyl group, ahaloalkyl group, a halogen atom such as F, Cl, Br, and I; an alkenyl, ahaloalkenyl group, an alkynyl group, a haloalkynyl group, a cyclic groupsuch as an aryl, heteroaryl, cycloalkyl, or heterocyclyl group, anoxygen atom in groups such as hydroxy groups, alkoxy groups, and estergroups; a sulfur atom in groups such as thiol groups, thioalkyl groups,thiohaloalkyl groups, sulfone groups, sulfonyl groups, and sulfoxidegroups; a nitrogen atom in groups such as amines, amides, alkylamines,dialkylamines, arylamines, alkylarylamines, diarylamines, N-oxides,imides, and enamines; a silicon atom in groups such as trialkylsilylgroups, dialkylarylsilyl groups, alkyldiarylsilyl groups, andtriarylsilyl groups; and other heteroatoms in various other groups.“Substituted” also means any of the above groups in which one or morehydrogen atoms are replaced by a higher-order bond (e.g., a double- ortriple-bond) to a heteroatom such as oxygen in oxo, carbonyl, formyl,carboxyl, carbonate, and ester groups; and nitrogen in groups such asimines, oximes, hydrazones, and nitriles.

In certain embodiments, “substituted” includes any of the above alkyl,alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl groups inwhich one or more hydrogen atoms are independently replaced withdeuterium, halo, cyano, nitro, azido, oxo, alkyl, alkenyl, alkynyl,haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, —NR^(g)R^(h),—NR^(g)C(═O)R^(h), —NR^(g)C(═O)NR^(g)R^(h), —NR^(g)C(═O)OR^(h),—NR^(g)S(═O)₁₋₂R^(h), —C(═O)R^(g), —C(═O)OR^(g), —OC(═O)OR^(g),—OC(═O)R^(g), —C(═O)NR^(g)R^(h), —OC(═O)NR^(g)R^(h), —OR^(g), —SR^(g),—S(═O)R^(g), —S(═O)₂R^(g), —OS(═O)₁₋₂R^(g), —S(═O)₁₋₂OR^(g),—NR^(g)S(═O)₁₋₂NR^(g)R^(h), ═NSO₂R⁹, ═NOR⁹, —S(═O)₁₋₂NR^(g)R^(h), —SF₅,—SCF₃ or —OCF₃. In certain embodiments, “substituted” also means any ofthe above groups in which one or more hydrogen atoms are replaced with—C(═O)R^(g), —C(═O)OR^(g), —C(═O)NR^(g)R^(h), —CH₂SO₂R^(g),—CH₂SO₂NR^(g)R^(h). In certain embodiments, “substituted” further meansany of the above groups in which one or more hydrogen atoms are replacedby —NR^(g)S(O)₁₋₂NR^(g)R^(h), —CH₂S(O)R^(g), —CH₂S(O)NR^(g)R^(h),—OC(═O)OR^(g), —SF₅, —SCF₃ or —OCF₃. In certain embodiments,“substituted” further means any of the above groups in which one or morehydrogen atoms are replaced by a bond to an amino, cyano, hydroxy,imino, nitro, oxo, thioxo, halo, alkyl, alkoxy, alkylamino, thioalkyl,aryl, aralkyl, cycloalkyl, cycloalkylalkyl, haloalkyl, heterocyclyl,N-heterocyclyl, heterocyclylalkyl, heteroaryl, and/or heteroarylalkylgroup. In the foregoing, R^(g) and R^(h) and R^(i) are the same ordifferent and independently hydrogen, halo, alkyl, alkenyl, alkynyl,alkoxy, thioalkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl,haloalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, and/orheteroarylalkyl, or two of R^(g) and R^(h) and R^(i) are taken togetherwith the atoms to which they are attached to form a heterocyclyl ringoptionally substituted with oxo, halo or alkyl optionally substitutedwith oxo, halo, amino, hydroxy or alkoxy. In an embodiment, each of saidalkyl, alkenyl, alkynyl, alkoxy, thioalkyl, aryl, aralkyl, cycloalkyl,cycloalkylalkyl, haloalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl,and/or heteroarylalkyl are independently optionally substituted with oneor more oxo, alkyl, halo, amino, hydroxy or alkoxy. In addition, each ofthe foregoing substituents may also be optionally substituted with oneor more of the above substituents.

Polymers or similar indefinite structures arrived at by definingsubstituents with further substituents appended ad infinitum (e.g., asubstituted aryl having a substituted alkyl which is itself substitutedwith a substituted aryl group, which is further substituted by asubstituted heteroalkyl group, etc.) are not intended for inclusionherein. Unless otherwise noted, the maximum number of serialsubstitutions in compounds described herein is three. For example,serial substitutions of substituted aryl groups with two othersubstituted aryl groups are limited to ((substituted aryl)substitutedaryl) substituted aryl. Similarly, the above definitions are notintended to include impermissible substitution patterns (e.g., methylsubstituted with 5 fluorines or heteroaryl groups having two adjacentoxygen ring atoms). Such impermissible substitution patterns are wellknown to the skilled artisan. When used to modify a chemical group, theterm “substituted” may describe other chemical groups defined herein.Unless specified otherwise, where a group is described as optionallysubstituted, any substituents of the group are themselves unsubstituted.For example, in certain embodiments, the term “substituted alkyl” refersto an alkyl group having one or more substituents including hydroxy,halo, alkoxy, acyl, oxo, amino, cycloalkyl, heterocyclyl, aryl, andheteroaryl. In other embodiments, the one or more substituents may befurther substituted with halo, alkyl, haloalkyl, hydroxy, alkoxy,cycloalkyl, heterocyclyl, aryl, or heteroaryl, each of which issubstituted. In other embodiments, the substituents may be furthersubstituted with halo, alkyl, haloalkyl, alkoxy, hydroxy, cycloalkyl,heterocyclyl, aryl, or heteroaryl, each of which is unsubstituted.

Any compound or formula given herein, is also intended to representunlabeled forms as well as isotopically labeled forms of the compounds.Isotopically labeled compounds have structures depicted by the formulasgiven herein except that one or more atoms are replaced by an atomhaving a selected atomic mass or mass number. Examples of isotopes thatcan be incorporated into compounds of the disclosure include isotopes ofhydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine and chlorine,such as, but not limited to ²H (deuterium, D), 3H (tritium), ¹¹C, ¹³C,¹⁴C, ¹⁵N, ¹⁸F, ³¹P, ³²p, ³⁵, ³⁶Cl and ¹²⁵I. Various isotopically labeledcompounds of the present disclosure, for example those into whichradioactive isotopes such as ³H, ¹³C and ¹⁴C are incorporated. Suchisotopically labelled compounds may be useful in metabolic studies,reaction kinetic studies, detection or imaging techniques, such aspositron emission tomography (PET) or single-photon emission computedtomography (SPECT) including drug or substrate tissue distributionassays or in radioactive treatment of patients.

The disclosure also includes “deuterated analogs” of compounds ofFormula I in which from 1 to n hydrogens attached to a carbon atomis/are replaced by deuterium, in which n is the number of hydrogens inthe molecule. Such compounds exhibit increased resistance to metabolismand are thus useful for increasing the half-life of any compound ofFormula I when administered to a mammal, particularly a human. See, forexample, Foster, “Deuterium Isotope Effects in Studies of DrugMetabolism,” Trends Pharmacol. Sci. 5(12):524-527 (1984). Such compoundsare synthesized by means well known in the art, for example by employingstarting materials in which one or more hydrogens have been replaced bydeuterium.

Deuterium labelled or substituted therapeutic compounds of thedisclosure may have improved DMPK (drug metabolism and pharmacokinetics)properties, relating to distribution, metabolism and excretion (ADME).Substitution with heavier isotopes such as deuterium may afford certaintherapeutic advantages resulting from greater metabolic stability, forexample increased in vivo half-life, reduced dosage requirements and/oran improvement in therapeutic index. An ¹⁸F, ³H, ¹¹C labeled compoundmay be useful for PET or SPECT or other imaging studies. Isotopicallylabeled compounds of this disclosure and prodrugs thereof can generallybe prepared by carrying out the procedures disclosed in the schemes orin the examples and preparations described below by substituting areadily available isotopically labeled reagent for a non-isotopicallylabeled reagent. It is understood that deuterium in this context isregarded as a substituent in the compound of Formula I.

The concentration of such a heavier isotope, specifically deuterium, maybe defined by an isotopic enrichment factor. In the compounds of thisdisclosure any atom not specifically designated as a particular isotopeis meant to represent any stable isotope of that atom. Unless otherwisestated, when a position is designated specifically as “H” or “hydrogen”,the position is understood to have hydrogen at its natural abundanceisotopic composition. Accordingly, in the compounds of this disclosureany atom specifically designated as a deuterium (D) is meant torepresent deuterium.

In many cases, the compounds of this disclosure are capable of formingacid and/or base salts by virtue of the presence of amino and/orcarboxyl groups or groups similar thereto.

Provided are also pharmaceutically acceptable salts, hydrates, solvates,tautomeric forms, stereoisomers, and prodrugs of the compounds describedherein. “Pharmaceutically acceptable” or “physiologically acceptable”refer to compounds, salts, compositions, dosage forms and othermaterials which are useful in preparing a pharmaceutical compositionthat is suitable for veterinary or human pharmaceutical use.

The term “pharmaceutically acceptable salt” of a given compound refersto salts that retain the biological effectiveness and properties of thegiven compound, and which are not biologically or otherwise undesirable.“Pharmaceutically acceptable salts” or “physiologically acceptablesalts” include, for example, salts with inorganic acids and salts withan organic acid. In addition, if the compounds described herein areobtained as an acid addition salt, the free base can be obtained bybasifying a solution of the acid salt. Conversely, if the product is afree base, an addition salt, particularly a pharmaceutically acceptableaddition salt, may be produced by dissolving the free base in a suitableorganic solvent and treating the solution with an acid, in accordancewith conventional procedures for preparing acid addition salts from basecompounds. Those skilled in the art will recognize various syntheticmethodologies that may be used to prepare nontoxic pharmaceuticallyacceptable addition salts. Pharmaceutically acceptable acid additionsalts may be prepared from inorganic and organic acids. Salts derivedfrom inorganic acids include hydrochloric acid, hydrobromic acid,sulfuric acid, nitric acid, phosphoric acid, and the like. Salts derivedfrom organic acids include acetic acid, propionic acid, glycolic acid,pyruvic acid, oxalic acid, malic acid, malonic acid, succinic acid,maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid,cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid,p-toluene-sulfonic acid, salicylic acid, and the like. Likewise,pharmaceutically acceptable base addition salts can be prepared frominorganic and organic bases. Salts derived from inorganic bases include,by way of example only, sodium, potassium, lithium, ammonium, calciumand magnesium salts. Salts derived from organic bases include, but arenot limited to, salts of primary, secondary and tertiary amines, such asalkyl amines (i.e., NH₂(alkyl)), dialkyl amines (i.e., HN(alkyl)₂),trialkyl amines (i.e., N(alkyl)₃), substituted alkyl amines (i.e.,NH₂(substituted alkyl)), di(substituted alkyl) amines (i.e.,HN(substituted alkyl)₂), tri(substituted alkyl) amines (i.e.,N(substituted alkyl)₃), alkenyl amines (i.e., NH₂(alkenyl)), dialkenylamines (i.e., HN(alkenyl)₂), trialkenyl amines (i.e., N(alkenyl)₃),substituted alkenyl amines (i.e., NH₂(substituted alkenyl)),di(substituted alkenyl) amines (i.e., HN(substituted alkenyl)₂),tri(substituted alkenyl) amines (i.e., N(substituted alkenyl)₃, mono-,di- or tri-cycloalkyl amines (i.e., NH₂(cycloalkyl), HN(cycloalkyl)₂,N(cycloalkyl)₃), mono-, di- or tri-arylamines (i.e., NH₂(aryl),HN(aryl)₂, N(aryl)₃), or mixed amines, etc. Specific examples ofsuitable amines include, by way of example only, isopropylamine,trimethyl amine, diethyl amine, tri(iso-propyl) amine, tri(n-propyl)amine, ethanolamine, 2-dimethylaminoethanol, piperazine, piperidine,morpholine, N-ethylpiperidine, and the like.

The term “hydrate” refers to the complex formed by the combining of acompound of Formula I and water.

A “solvate” refers to an association or complex of one or more solventmolecules and a compound of the invention. Examples of solvents thatform solvates include, but are not limited to, water, isopropanol,ethanol, methanol, dimethylsulfoxide, ethylacetate, acetic acid, andethanolamine.

Some of the compounds exist as tautomers. Tautomers are in equilibriumwith one another. For example, amide containing compounds may exist inequilibrium with imidic acid tautomers. Regardless of which tautomer isshown, and regardless of the nature of the equilibrium among tautomers,the compounds are understood by one of ordinary skill in the art tocomprise both amide and imidic acid tautomers. Thus, the amidecontaining compounds are understood to include their imidic acidtautomers. Likewise, the imidic acid containing compounds are understoodto include their amide tautomers.

The compounds disclosed herein, or their pharmaceutically acceptablesalts include an asymmetric center and may thus give rise toenantiomers, diastereomers, and other stereoisomeric forms that may bedefined, in terms of absolute stereochemistry, as (R)- or (S)- or, as(D)- or (L)- for amino acids. The disclosure is meant to include allsuch possible isomers, as well as their racemic and optically pureforms. Optically active (+) and (−), (R)- and (S)-, or (D)- and(L)-isomers may be prepared using chiral synthons or chiral reagents, orresolved using conventional techniques, for example, chromatography andfractional crystallization. Conventional techniques for thepreparation/isolation of individual enantiomers include chiral synthesisfrom a suitable optically pure precursor or resolution of the racemate(or the racemate of a salt or derivative) using, for example, chiralhigh pressure liquid chromatography (HPLC). When the compounds describedherein contain olefinic double bonds or other centres of geometricasymmetry, and unless specified otherwise, it is intended that thecompounds include both E and Z geometric isomers. Likewise, alltautomeric forms are also intended to be included.

“Stereoisomers” are isomers that differ only in the way the atoms arearranged in space and include enantiomers and diastereomers. In certainembodiments, a “stereoisomer” refers to a compound made up of the sameatoms bonded by the same bonds but having different three-dimensionalstructures, which are not interchangeable. The present disclosurecontemplates various stereoisomers and mixtures thereof and includes“enantiomers,” which refers to two stereoisomers whose molecules arenonsuperimposeable mirror images of one another.

“Enantiomers” are a pair of stereoisomers that are non-superimposablemirror images of each other. A 1:1 mixture of a pair of enantiomers is a“racemic” mixture.

“Diastereoisomers” are stereoisomers that have at least two asymmetricatoms, but which are not mirror-images of each other.

The absolute stereochemistry is specified according to the Cahn IngoldPrelog R S system. When the compound is a pure enantiomer thestereochemistry at each chiral carbon may be specified by either R or S.Resolved compounds whose absolute configuration is unknown aredesignated (+) or (−) depending on the direction (dextro- orlaevorotary) that they rotate the plane of polarized light at thewavelength of the sodium D line.

“Prodrugs” means any compound which releases an active parent drugaccording to Formula I or any other formula described herein in vivowhen such prodrug is administered to a mammalian subject. Prodrugs of acompound of Formula I or any other formula described herein are preparedby modifying functional groups present in the compound of Formula I orany other formula described herein in such a way that the modificationsmay be cleaved in vivo to release the parent compound. Prodrugs may beprepared by modifying functional groups present in the compounds in sucha way that the modifications are cleaved, either in routine manipulationor in vivo, to the parent compounds. Prodrugs include compounds ofFormula I or any other formula described herein wherein a hydroxy,amino, carboxyl or sulfhydryl group in a compound of Formula I or anyother formula described herein is bonded to any group that may becleaved in vivo to regenerate the free hydroxy, amino, or sulfhydrylgroup, respectively. Examples of prodrugs include, but are not limitedto esters (e.g., acetate, formate and benzoate derivatives), amides,guanidines, carbamates (e.g., N,N-dimethylaminocarbonyl) of hydroxyfunctional groups in compounds of Formula I or any other formuladescribed herein and the like. Preparation, selection and use ofprodrugs is discussed in T. Higuchi and V. Stella, “Pro-drugs as NovelDelivery Systems,” Vol. 14 of the A.C.S. Symposium Series; “Design ofProdrugs”, ed. H. Bundgaard, Elsevier, 1985; and in BioreversibleCarriers in Drug Design, ed. Edward B. Roche, American PharmaceuticalAssociation and Pergamon Press, 1987, each of which are herebyincorporated by reference in their entirety.

As used herein, “pharmaceutically acceptable carrier” or“pharmaceutically acceptable excipient” or “excipient” includes any andall solvents, dispersion media, coatings, antibacterial and antifungalagents, isotonic and absorption delaying agents and the like. The use ofsuch media and agents for pharmaceutically active substances is wellknown in the art. Except insofar as any conventional media or agent isincompatible with the active ingredient, its use in the therapeuticcompositions is contemplated. Supplementary active ingredients can alsobe incorporated into the compositions.

2. List of Abbreviations and Acronyms

List of Abbreviations and Acronyms Abbreviation Meaning aq. Aqueous BOCtert-butyloxycarbonyl br Broad d Doublet DAD Diode array detector DASTDiethylaminosulfur trifluoride dd doublet of doublets ddd doublet ofdoublet of doublets dddd doublet of doublet of doublet of doublets dtDoublet of triplets DIPEA/DIEA Diisopropylethylamine DMFDimethylformamide DMSO Dimethylsulfoxide ee/e.e. Enantiomer excess ESElectrospray ESI Electrospray ion source Et Ethyl EtOH Ethanol EtOACEthyl acetate HATU 1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5- b]pyridinium 3-oxid hexafluorophosphate HBTUN,N,N′,N′-Tetramethyl-O- (1H-benzotriazol-1-yl)uroniumhexafluorophosphate HOBt 1-hydroxybenzotriazole HPLC High pressureliquid chromatography hrs/h Hours Hz Hertz J Coupling constant (MHz)LCMS/LC- Liquid chromatography-mass MS spectrometry M Molar MeCNAcetonitrile MeOH Methanol m Multiplet (when used with a J) m/zMass-to-charge ratio [M + H]⁺ Mass peak plus hydrogen min Minute(s) MSMass spectrometry N Normal NCS N-Chlorosuccinimide NMR Nuclear magneticresonance o/n Overnight PDA Photodiode array detector quin Quintuplet rtRoom temperature s Singlet (when used with J) s Second(s) sat. Saturatedt Triplet THF Tetrahydrofuran TFA Trifluoroacetic acid TIC Total ioncurrent TLC Thin layer chromatography TMEDA N,N,N′,N′,-Tetramethylethylenediamine TMIS Iodotrimethylsilane v/v Volume/volume δChemical shift (ppm)

3. Compounds

Provided herein are compounds that are useful as inhibitors ofreceptor-interacting protein kinase 1. In certain embodiments, providedis a compound of Formula I:

or a pharmaceutically acceptable salt, prodrug, tautomer, stereoisomeror mixture of stereoisomers thereof;

wherein

Y¹ is O or NR²;

X¹ and X² are each independently nitrogen or carbon and either

-   -   X¹ and X² together form an optionally substituted cycloalkyl,        optionally substituted heterocyclyl, optionally substituted        aryl, or optionally substituted heteroaryl and R¹ is H or C₁-C₆        alkyl optionally substituted with halo, hydroxy or cyano or when        Y¹ is NR², then R² and R¹ together with the nitrogen atoms to        which they are attached, form an optionally substituted        heterocyclyl or optionally substituted heteroaryl ring, or    -   X¹ and R¹ together with the atoms to which they are attached,        form an optionally substituted heterocyclyl or optionally        substituted heteroaryl ring, and X² is —CH₂—;

Y² is —O—, —S—, —S(O)—, —S(O)₂—, —S(O)(NH)—, —NR⁵— or —C(R⁶)₂—;

R⁵ is H or optionally substituted C₁-C₆ alkyl;

Y² is —O—, —S—, —S(O)—, —S(O)₂—, —S(O)(NH)—, —NR⁵— or —C(R⁶)₂—;

R⁵ is H or optionally substituted C₁-C₆ alkyl;

each R⁶ is independently H, halo, or optionally substituted C₁-C₆ alkyl,or two R⁶ together with the carbon atom to which they are attached, forma C₁-C₆ alken-1-yl, optionally substituted cycloalkyl or optionallysubstituted heterocyclyl ring;

R³ and R⁴ are independently H, halo, or optionally substituted C₁-C₆alkyl, or R³ and R⁴ together with the carbon atoms to which they areattached, form an optionally substituted cycloalkyl or optionallysubstituted heterocyclyl ring, or R³ and R⁶ together with the carbonatoms to which they are attached, form an optionally substitutedcycloalkyl or optionally substituted heterocyclyl ring;

A is an optionally substituted cycloalkyl, optionally substitutedheterocyclyl, optionally substituted aryl or optionally substitutedheteroaryl ring;

L is absent, —O—, —S—, —S(O)—, —S(O)₂—, —NR⁷— or —C(R⁸)₂—;

R⁷ is H or optionally substituted C₁-C₆ alkyl;

each R⁸ is independently H, halo, or optionally substituted C₁-C₆ alkyl,or two R⁸ together with the carbon atom to which they are attached, forma optionally substituted cycloalkyl or optionally substitutedheterocyclyl ring; and

R⁹ is optionally substituted cycloalkyl, optionally substitutedheterocyclyl, optionally substituted aryl or optionally substitutedheteroaryl;

provided that when the moiety

is

and the aromatic ring is optionally substituted then at least one of thefollowing occurs:

(1) L is absent or —C(R⁸)₂—, and each R⁸ is optionally substituted C₁-C₆alkyl or halo, or two R⁸ together with the carbon atom to which they areattached, form an optionally substituted cycloalkyl or optionallysubstituted heterocyclyl ring;

(2) Y² is —C(R⁶)₂— and at least one R⁶ is other than hydrogen;

(3) Y² is —O— and A is substituted with halo or cyano or A is thiazolylor a 3- or 4-membered ring;

(4) Y² is —S—, —S(O)—, or —S(O)₂—; and A is other than isoxazole andphenyl or Y² is —S(O)(NH)—;

(5) Y² is —NR⁵— and A is other than isoxazole, pyrazole and triazole;

(6) the carbonyl moiety and L are substituted other than 1,3- on ring A;or

(7) R⁹ is substituted cycloalkyl, substituted heterocyclyl, substitutedaryl or substituted heteroaryl, wherein at least one substituent iscyano;

(8) R¹ is C₂-C₆ alkyl optionally substituted with halo, hydroxy orcyano; or

(9) when X¹ and X² form an optionally substituted phenyl ring as in themoiety

at least one substituent is at the 1 or 4 position and is (a) other thanfluoro, chloro or methyl at the 1 position, and/or (b) other than fluoroor methyl for the 4 position; and further provided the moiety

is not

wherein the nitrogen containing aromatic ring is optionally substituted;

and with the further proviso that the compound is not:5-(difluoro(phenyl)methyl)-N-(4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)isoxazole-3-carboxamide;5-(difluoro(phenyl)methyl)-N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)isoxazole-3-carboxamide;2-(4-bromobenzyl)-N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)thiazole-4-carboxamide;2-benzyl-N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)thiazole-4-carboxamide;4-(1,4-dihydro-2-oxo-3(2H)-quinazolinyl)-N-[2,3,4,5-tetrahydro-1-(1-methylethyl)-2-oxo-1H-1-benzazepin-3-yl]-1-piperidinecarboxamide;4-(2-amino-7-chloro-4-quinolinyl)-N-[(3S)-2,3,4,5-tetrahydro-2-oxo-1H-1-benzazepin-3-yl]-1-piperazinecarboxamide;or4-(2-aino-7-chloro-4-quinolinyl)-N-[(3S)-2,3,4,5-tetrahydro-1-methyl-2-oxo-1H-1-benzazepin-3-yl]-1-piperazinecarboxamide.

In certain embodiments, provided is a compound of Formula I or apharmaceutically acceptable salt, prodrug, tautomer, stereoisomer ormixture of stereoisomers thereof

wherein

Y¹ is O or NR²;

X¹ and X² are each independently nitrogen or carbon and either

-   -   X¹ and X² together form an optionally substituted cycloalkyl,        optionally substituted heterocyclyl, optionally substituted        aryl, or optionally substituted heteroaryl and R¹ is H or C₁-C₆        alkyl optionally substituted with halo, hydroxy or cyano or when        Y¹ is NR², then R² and R¹ together with the nitrogen atoms to        which they are attached, form an optionally substituted        heterocyclyl or optionally substituted heteroaryl ring, or    -   X¹ and R¹ together with the atoms to which they are attached,        form an optionally substituted heterocyclyl or optionally        substituted heteroaryl ring, and X² is —CH₂—;

Y² is —O—, —S—, —S(O)—, —S(O)₂—, —S(O)(NH)—, —NR⁵— or —C(R⁶)₂—;

R⁵ is H or optionally substituted C₁-C₆ alkyl;

each R⁶ is independently H, halo, or optionally substituted C₁-C₆ alkyl,or two R⁶ together with the carbon atom to which they are attached, forma C₁-C₆ alken-1-yl, optionally substituted cycloalkyl or optionallysubstituted heterocyclyl ring;

R³ and R⁴ are independently H, halo, or optionally substituted C₁-C₆alkyl, or R³ and R⁴ together with the carbon atoms to which they areattached, form an optionally substituted cycloalkyl or optionallysubstituted heterocyclyl ring, or R³ and R⁶ together with the carbonatoms to which they are attached, form an optionally substitutedcycloalkyl or optionally substituted heterocyclyl ring;

A is an optionally substituted cycloalkyl, optionally substitutedheterocyclyl, optionally substituted aryl or optionally substitutedheteroaryl ring;

L is absent, —O—, —S—, —S(O)—, —S(O)₂—, —NR⁷— or —C(R⁸)₂—;

R⁷ is H or optionally substituted C₁-C₆ alkyl;

each R⁸ is independently H, halo, or optionally substituted C₁-C₆ alkyl,or two R⁸ together with the carbon atom to which they are attached, forma optionally substituted cycloalkyl or optionally substitutedheterocyclyl ring; and

R⁹ is optionally substituted cycloalkyl, optionally substitutedheterocyclyl, optionally substituted aryl or optionally substitutedheteroaryl;

-   -   provided that when the moiety

is

and the aromatic ring is optionally substituted then at least one of thefollowing occurs:

(1) L is absent or —C(R⁸)₂—, and each R⁸ is optionally substituted C₁-C₆alkyl or halo, or two R⁸ together with the carbon atom to which they areattached, form an optionally substituted cycloalkyl or optionallysubstituted heterocyclyl ring;

(2) Y² is —C(R⁶)₂— and at least one R⁶ is other than hydrogen;

(3) Y² is —O— and A is substituted with halo or cyano or A is thiazolylor a 3- or 4-membered ring;

(4) Y² is —S—, —S(O)—, or —S(O)₂—; and A is other than isoxazole andphenyl or Y² is —S(O)(NH)—;

(5) Y² is —NR⁵— and A is other than isoxazole, pyrazole and triazole; or

(6) the carbonyl moiety and L are substituted other than 1,3- on ring A;

(7) R¹ is C₂-C₆ alkyl optionally substituted with halo, hydroxy orcyano; or

(8) when X¹ and X² form an optionally substituted phenyl ring as in themoiety

at least one substituent is at the 1 or 4 position and is (a) other thanfluoro, chloro or methyl at the 1 position, and/or (b) other than fluoroor methyl for the 4 position; and further provided the moiety

is not

wherein the nitrogen containing aromatic ring is optionally substituted;

and with the further proviso that the compound is not:5-(difluoro(phenyl)methyl)-N-(4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)isoxazole-3-carboxamide;5-(difluoro(phenyl)methyl)-N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)isoxazole-3-carboxamide;2-(4-bromobenzyl)-N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)thiazole-4-carboxamide;2-benzyl-N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)thiazole-4-carboxamide;4-(1,4-dihydro-2-oxo-3(2H)-quinazolinyl)-N-[2,3,4,5-tetrahydro-1-(1-methylethyl)-2-oxo-1H-1-benzazepin-3-yl]-1-piperidinecarboxamide;4-(2-amino-7-chloro-4-quinolinyl)-N-[(3S)-2,3,4,5-tetrahydro-2-oxo-1H-1-benzazepin-3-yl]-1-piperazinecarboxamide;or4-(2-amino-7-chloro-4-quinolinyl)-N-[(3S)-2,3,4,5-tetrahydro-1-methyl-2-oxo-1H-1-benzazepin-3-yl]-1-piperazinecarboxamide.

In certain embodiments, at least one of R³ and R⁴ are halo or optionallysubstituted C₁-C₆ alkyl, or R³ and R⁴ together with the carbon atoms towhich they are attached, form an optionally substituted cycloalkyl oroptionally substituted heterocyclyl ring, or R³ and R⁶ together with thecarbon atoms to which they are attached, form a optionally substitutedcycloalkyl or optionally substituted heterocyclyl ring.

In certain embodiments, L is absent or —C(R⁸)₂—, and each R isoptionally substituted C₁-C₆ alkyl or halo, or two R⁸ together with thecarbon atom to which they are attached, form an optionally substitutedcycloalkyl or optionally substituted heterocyclyl ring.

In certain embodiments, Y¹ is NR².

In certain embodiments, X¹ and X² are each independently nitrogen orcarbon, and together form a 5 membered optionally substitutedcycloalkyl, optionally substituted heterocyclyl, optionally substitutedaryl, or optionally substituted heteroaryl.

In certain embodiments, X¹ and R¹ together with the atoms to which theyare attached, form a 5 or 6 membered optionally substituted heterocyclylor optionally substituted heteroaryl ring; and X² is —CH₂—.

In certain embodiments, Y² is —C(R⁶)₂—; and one R⁶ is hydrogen, halo, oroptionally substituted C₁-C₆ alkyl, and the other R⁶ is halo oroptionally substituted C₁-C₆ alkyl; or two R⁶ together with the carbonatom to which they are attached, form a C₁-C₆ alken-1-yl, optionallysubstituted cycloalkyl or optionally substituted heterocyclyl ring.

In certain embodiments, Y² is —O— and A is substituted with halo orcyano; or A is thiazolyl or a 3- or 4-membered ring.

In certain embodiments, Y² is —S—, —S(O)—, or —S(O)₂—; and A is otherthan isoxazole and phenyl or Y² is —S(O)(NH)—.

In certain embodiments, Y² is —NR⁵—; X¹ and X² together form anoptionally substituted phenyl, and A is other than isoxazole, pyrazoleand triazole; X¹ and X² together form an optionally substituted pyridyl,and A is other than triazole; or X¹ and X² are optionally substitutedpyrimidyl, and A is other than pyrazole and triazole.

In certain embodiments, the carbonyl moiety and L are substituted otherthan 1,3- on ring A.

In certain embodiments, provided is a compound of Formula I or apharmaceutically acceptable salt, prodrug, tautomer, stereoisomer ormixture of stereoisomers thereof;

wherein

Y¹ is O or NR²;

X¹ and X² are each independently nitrogen or carbon and either

-   -   X¹ and X² together form an optionally substituted cycloalkyl,        optionally substituted heterocyclyl, optionally substituted        aryl, or optionally substituted heteroaryl and R¹ is H or C₁-C₆        alkyl optionally substituted with halo, hydroxy or cyano or when        Y¹ is NR², then R² and R¹ together with the nitrogen atoms to        which they are attached, form an optionally substituted        heterocyclyl or optionally substituted heteroaryl ring, or    -   X¹ and R¹ together with the atoms to which they are attached,        form an optionally substituted heterocyclyl or optionally        substituted heteroaryl ring, and X² is —CH₂—;

Y² is —O—, —S—, —S(O)—, —S(O)₂—, —S(O)(NH)—, —NR⁵— or —C(R⁶)₂—;

R⁵ is H or optionally substituted C₁-C₆ alkyl;

each R⁶ is independently H, halo, or optionally substituted C₁-C₆ alkyl,or two R⁶ together with the carbon atom to which they are attached, forma C₁-C₆ alken-1-yl, optionally substituted cycloalkyl or optionallysubstituted heterocyclyl ring;

R³ and R⁴ are independently H, halo, or optionally substituted C₁-C₆alkyl, or R³ and R⁴ together with the carbon atoms to which they areattached, form an optionally substituted cycloalkyl or optionallysubstituted heterocyclyl ring, or R³ and R⁶ together with the carbonatoms to which they are attached, form an optionally substitutedcycloalkyl or optionally substituted heterocyclyl ring;

A is an optionally substituted cycloalkyl, optionally substitutedheterocyclyl, optionally substituted aryl or optionally substitutedheteroaryl ring;

L is absent, —O—, —S—, —S(O)—, —S(O)₂—, —NR⁷— or —C(R⁸)₂—;

R⁷ is H or optionally substituted C₁-C₆ alkyl;

each R⁸ is independently H, halo, or optionally substituted C₁-C₆ alkyl,or two R⁸ together with the carbon atom to which they are attached, forma optionally substituted cycloalkyl or optionally substitutedheterocyclyl ring; and

R⁹ is optionally substituted cycloalkyl, optionally substitutedheterocyclyl, optionally substituted aryl or optionally substitutedheteroaryl;

-   -   provided that at least one of the following occurs:

(1) at least one of R³ and R⁴ are halo or optionally substituted C₁-C₆alkyl, or R³ and R⁴ together with the carbon atoms to which they areattached, form an optionally substituted cycloalkyl or optionallysubstituted heterocyclyl ring, or R³ and R⁶ together with the carbonatoms to which they are attached, form a optionally substitutedcycloalkyl or optionally substituted heterocyclyl ring;

(2) L is absent or —C(R⁸)₂—, and each R⁸ is optionally substituted C₁-C₆alkyl or halo, or two R⁸ together with the carbon atom to which they areattached, form an optionally substituted cycloalkyl or optionallysubstituted heterocyclyl ring;

(3) Y¹ is NR²;

(4) X¹ and X² are each independently nitrogen or carbon, and togetherform a 5 membered optionally substituted cycloalkyl, optionallysubstituted heterocyclyl, optionally substituted aryl, or optionallysubstituted heteroaryl;

(5) X¹ and R¹ together with the atoms to which they are attached, form a5 or 6 membered optionally substituted heterocyclyl or optionallysubstituted heteroaryl ring; and X² is —CH₂—;

(6) Y² is —C(R⁶)₂—; and one R⁶ is hydrogen, halo, or optionallysubstituted C₁-C₆ alkyl, and the other R⁶ is halo or optionallysubstituted C₁-C₆ alkyl; or two R⁶ together with the carbon atom towhich they are attached, form a C₁-C₆ alken-1-yl, optionally substitutedcycloalkyl or optionally substituted heterocyclyl ring;

(7) Y² is —O—; and A is substituted with halo or cyano; or A isthiazolyl or a 3- or 4-membered ring;

(8) Y² is —S—, —S(O)—, or —S(O)₂—; and A is other than isoxazole andphenyl or Y² is —S(O)(NH)—;

(9) Y² is —NR⁵—; X¹ and X² together form an optionally substitutedphenyl, and A is other than isoxazole, pyrazole and triazole; X¹ and X²together form an optionally substituted pyridyl, and A is other thantriazole; or X¹ and X² are optionally substituted pyrimidyl, and A isother than pyrazole and triazole;

(10) the carbonyl moiety and L are substituted other than 1,3- on ringA;

(11) Y² is —O—; X¹ and X² together form an optionally substitutedpyridyl, and A is other than isoxazole;

(12) R¹ is C₂-C₆ alkyl optionally substituted with halo, hydroxy orcyano; or

(13) when X¹ and X² form an optionally substituted phenyl ring as in themoiety

at least one substituent is at the 1 or 4 position and is (a) other thanfluoro, chloro or methyl at the 1 position, and/or (b) other than fluoroor methyl for the 4 position;

and with the further proviso that the compound is not:5-(difluoro(phenyl)methyl)-N-(4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)isoxazole-3-carboxamide;5-(difluoro(phenyl)methyl)-N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)isoxazole-3-carboxamide;2-(4-bromobenzyl)-N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)thiazole-4-carboxamide;2-benzyl-N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)thiazole-4-carboxamide;4-(1,4-dihydro-2-oxo-3(2H)-quinazolinyl)-N-[2,3,4,5-tetrahydro-1-(1-methylethyl)-2-oxo-1H-1-benzazepin-3-yl]-1-piperidinecarboxamide;4-(2-amino-7-chloro-4-quinolinyl)-N-[(3S)-2,3,4,5-tetrahydro-2-oxo-1H-1-benzazepin-3-yl]-1-piperazinecarboxamide;or4-(2-amino-7-chloro-4-quinolinyl)-N-[(3S)-2,3,4,5-tetrahydro-1-methyl-2-oxo-1H-1-benzazepin-3-yl]-1-piperazinecarboxamide.

In certain embodiments, the compound is not5-(difluorophenylmethyl)-N-[(3S)-2,3,4,5-tetrahydro-5-methyl-4-oxo-1,5-benzoxazepin-3-yl]-3-isoxazolecarboxamideor5-(difluorophenylmethyl)-N-[(3S)-2,3,4,5-tetrahydro-4-oxo-1,5-benzoxazepin-3-yl]-3-isoxazolecarboxamide.

Also provided herein are compounds that are useful as inhibitors ofreceptor-interacting protein kinase 1. In certain embodiments, providedis a compound of Formula I wherein

R¹ is H or optionally substituted C₁-C₆ alkyl;

(a) X¹ and X² are each independently nitrogen or carbon, and togetherform an optionally substituted cycloalkyl, optionally substitutedheterocyclyl, optionally substituted aryl, or optionally substitutedheteroaryl; or

(b) X¹ and R¹ together with the atoms to which they are attached, forman optionally substituted heterocyclyl or optionally substitutedheteroaryl ring; and X² is —CH₂—;

Y¹ is O or NR², where R² and R¹ together with the nitrogen atoms towhich they are attached, form an optionally substituted heterocyclyl oroptionally substituted heteroaryl ring;

Y² is —O—, —S—, —S(O)—, —S(O)₂—, —S(O)(NH)—, —NR⁵— or —C(R⁶)₂—;

R⁵ is H or optionally substituted C₁-C₆ alkyl;

each R⁶ is independently H, halo, optionally substituted C₁-C₆ alkyl, ortwo R⁶ together with the carbon atom to which they are attached, form aC₁-C₆ alken-1-yl, optionally substituted cycloalkyl or optionallysubstituted heterocyclyl ring;

R³ and R⁴ are independently H, halo, optionally substituted C₁-C₆ alkyl,R³ and R⁴ together with the carbon atoms to which they are attached,form an optionally substituted cycloalkyl or optionally substitutedheterocyclyl ring, or R³ and R⁶ together with the carbon atoms to whichthey are attached, form an optionally substituted cycloalkyl oroptionally substituted heterocyclyl ring;

A is an optionally substituted cycloalkyl, optionally substitutedheterocyclyl ring or optionally substituted heteroaryl ring;

L is absent, —O—, —S—, —S(O)—, —S(O)₂—, —NR⁷— or —C(R⁸)₂—;

R⁷ is H or optionally substituted C₁-C₆ alkyl;

each R⁸ is independently H, halo, optionally substituted C₁-C₆ alkyl, ortwo R⁸ together with the carbon atom to which they are attached, form aoptionally substituted cycloalkyl or optionally substituted heterocyclylring; and

R⁹ is optionally substituted cycloalkyl, optionally substitutedheterocyclyl, optionally substituted aryl or optionally substitutedheteroaryl;

provided that at least one of the following occurs:

(1) at least one of R³ and R⁴ are halo or optionally substituted C₁-C₆alkyl, R³ and R⁴ together with the carbon atoms to which they areattached, form an optionally substituted cycloalkyl or optionallysubstituted heterocyclyl ring, or R³ and R⁶ together with the carbonatoms to which they are attached, form a optionally substitutedcycloalkyl or optionally substituted heterocyclyl ring;

(2) L is absent or —C(R⁸)₂—, and each R⁸ is optionally substituted C₁-C₆alkyl or halo provided that the compound is not5-(difluoro(phenyl)methyl)-N-(4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)isoxazole-3-carboxamideor not5-(difluoro(phenyl)methyl)-N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)isoxazole-3-carboxamideor two R⁸ together with the carbon atom to which they are attached, forman optionally substituted cycloalkyl or optionally substitutedheterocyclyl ring;

(3) Y¹ is NR²;

(4) X¹ and X² are each independently nitrogen or carbon, and togetherform a 5 membered optionally substituted cycloalkyl, optionallysubstituted heterocyclyl, optionally substituted aryl, or optionallysubstituted heteroaryl;

(5) X¹ and R¹ together with the atoms to which they are attached, form a5 or 6 membered optionally substituted heterocyclyl or optionallysubstituted heteroaryl ring; and X² is —CH₂—;

(6) Y² is —C(R⁶)₂—; and one R⁶ is hydrogen, halo, or optionallysubstituted C₁-C₆ alkyl, and the other R⁶ is halo or optionallysubstituted C₁-C₆ alkyl; or two R⁶ together with the carbon atom towhich they are attached, form a C₁-C₆ alken-1-yl, optionally substitutedcycloalkyl or optionally substituted heterocyclyl ring;

(7) Y² is —O—; and A is substituted with halo or cyano; or A isthiazolyl or a 3- or 4-membered ring; provided that the compound is not2-(4-bromobenzyl)-N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)thiazole-4-carboxamideor2-benzyl-N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)thiazole-4-carboxamide;

(8) Y² is —S—, —S(O)—, or —S(O)₂—; and A is other than 1,3-isoxazole orY² is —S(O)N(H)—;

(9) Y² is —NR⁵—; X¹ and X² together form an optionally substitutedphenyl, and A is other than isoxazole, pyrazole and triazole; X¹ and X²together form an optionally substituted pyridyl, and A is other thantriazole; or X¹ and X² are optionally substituted pyrimidyl, and A isother than pyrazole and triazole; or

(10) the carbonyl moiety and L are substituted other than 1,3- on ringA;

-   -   or a pharmaceutically acceptable salt, prodrug, tautomer,        stereoisomer or mixture of stereoisomers thereof.

In certain embodiments, R¹ is C₁-C₆ alkyl. In certain embodiments, R¹ ismethyl.

In certain embodiments, the moiety:

wherein

X³, X⁴ and X⁵ are each S, O, N, NH, or CH;

X⁶, X⁷, X⁸ and X⁹ are each N or CH;

q is 0, 1 or 2;

each R¹⁰ is independently cyano, halo, optionally substituted C₁-C₆alkyl or —S(O)₂—C₁-C₆ alkyl.

In certain embodiments, the moiety:

wherein

X³, X⁴ and X⁵ are each S, O, N, NH, or CH;

X⁶, X⁷, X⁸ and X⁹ are each N or CH;

q is 0, 1 or 2;

each R¹⁰ is independently cyano, halo or optionally substituted alkyl.

In certain embodiments, the moiety:

wherein

X³, X⁴ and X⁵ are each S, O, N, NH, or CH;

X⁶, X⁷, X⁸ and X⁹ are each N or CH;

q is 0, 1 or 2;

each R¹⁰ is independently halo or optionally substituted alkyl.

In certain embodiments, the moiety:

In certain embodiments, the moiety

is

In certain embodiments, the moiety

is

In certain embodiments, the moiety

is

In certain embodiments, Y¹ is O.

In certain embodiments, R¹ is methyl. In certain embodiments, R isethyl.

In certain embodiments, Y² is

where n is 1, 2, 3 or 4,

In certain embodiments, Y² is —O—; and A is substituted with halo orcyano; or A is thiazolyl or a 3- or 4-membered cycloalkyl or 3- or4-membered heterocycloalkyl ring.

In certain embodiments, both R³ and R⁴ are fluoro, or either R³ or R⁴are fluoro and the other is hydrogen, or R³ and R⁴ form a cyclopropyl orR³ joins with R⁶ to form a cyclopropyl. In certain embodiments, R³ or R⁴is methyl.

In certain embodiments, A is phenyl, phenylbenzo[d]thiazolyl,isoxazolyl, oxazolyl, pyrazolyl, triazolyl,5,6-dihydro-4H-pyrrolo[1,2-b]pyrazolyl, pyrrolyl, thiazolyl, imidazolyl,thiadiazolyl, cyclobutyl, cyclopropyl, or azetidinyl.

In certain embodiments, A is isoxazolyl, oxazolyl, pyrazolyl, triazolyl,5,6-dihydro-4H-pyrrolo[1,2-b]pyrazolyl, pyrrolyl, thiazolyl, imidazolyl,thiadiazolyl, cyclobutyl, cyclopropyl, or azetidinyl.

In certain embodiments, A is phenyl.

In certain embodiments, L is absent, —S(O)₂— or —C(R⁸)₂—.

In certain embodiments, two R⁸ together with the carbon atom to whichthey are attached, form an optionally substituted cycloalkyl oroptionally substituted heterocyclyl ring.

In certain embodiments, R⁹ is phenyl or 2,3-dihydro-1H-indenyl. Incertain embodiments, R⁹ is phenyl. In certain embodiments, R⁹ is2-F-phenyl. In certain embodiments, R⁹ is pyridyl. In certainembodiments, R⁹ is optionally substituted pyridyl, phenyl or2,3-dihydro-1H-indenyl.

In certain embodiments, q is 0. In certain embodiments, q is 1. Incertain embodiments, R¹⁰ is methyl.

In one aspect, provided is a compound of Formula Ia:

or a pharmaceutically acceptable salt, prodrug, tautomer, stereoisomeror mixture of stereoisomers thereof;

wherein

Y¹ is O or NR²;

X¹ and X² are each independently nitrogen or carbon and either

-   -   X¹ and X² together form an optionally substituted cycloalkyl,        optionally substituted heterocyclyl, optionally substituted        aryl, or optionally substituted heteroaryl and R¹ is H or C₁-C₆        alkyl optionally substituted with halo, hydroxy or cyano or when        Y¹ is NR², then R² and R¹ together with the nitrogen atoms to        which they are attached, form an optionally substituted        heterocyclyl or optionally substituted heteroaryl ring, or    -   X¹ and R¹ together with the atoms to which they are attached,        form an optionally substituted heterocyclyl or optionally        substituted heteroaryl ring, and X² is —CH₂—;

Y² is —O—, —S—, —S(O)—, —S(O)₂—, —S(O)(NH)—, —NR⁵— or —C(R⁶)₂—;

R⁵ is H or optionally substituted C₁-C₆ alkyl;

each R⁶ is independently H, halo, or optionally substituted C₁-C₆ alkyl,or two R⁶ together with the carbon atom to which they are attached, forma C₁-C₆ alken-1-yl, optionally substituted cycloalkyl or optionallysubstituted heterocyclyl ring;

R³ and R⁴ are independently H, halo, or optionally substituted C₁-C₆alkyl, or R³ and R⁴ together with the carbon atoms to which they areattached, form an optionally substituted cycloalkyl or optionallysubstituted heterocyclyl ring, or R³ and R⁶ together with the carbonatoms to which they are attached, form an optionally substitutedcycloalkyl or optionally substituted heterocyclyl ring;

A is an optionally substituted cycloalkyl, optionally substitutedheterocyclyl, optionally substituted aryl or optionally substitutedheteroaryl ring;

L is absent, —O—, —S—, —S(O)—, —S(O)₂—, —NR⁷— or —C(R⁸)₂—;

R⁷ is H or optionally substituted C₁-C₆ alkyl;

each R⁸ is independently H, halo, or optionally substituted C₁-C₆ alkyl,or two R⁸ together with the carbon atom to which they are attached, forma optionally substituted cycloalkyl or optionally substitutedheterocyclyl ring; and

R⁹ is optionally substituted cycloalkyl, optionally substitutedheterocyclyl, optionally substituted aryl or optionally substitutedheteroaryl.

In certain embodiments, the moiety

is

In certain embodiments, when the moiety

is

q is 0 or R¹⁰ is halo or alkyl, and L is absent, then ring A is a 3-, 4-or 5-membered monocyclic ring. In certain embodiments, the moiety

is

and when the moiety

is

q is 0 or R¹⁰ is halo or alkyl, and L is absent, then ring A is a 3-, 4-or 5-membered monocyclic ring.

In certain embodiments, in any Formula disclosed herein, R⁹ issubstituted with at least one cyano.

In certain embodiments, the compound is of Formula II:

or a pharmaceutically acceptable salt, prodrug, tautomer, stereoisomeror mixture of stereoisomers thereof;

wherein

q is 0, 1, or 2;

X⁶, X⁷, X⁸ and X⁹ are each N or CH;

R¹ is H or C₁-C₆ alkyl optionally substituted with halo, hydroxy orcyano;

Y² is —O—, —S—, —S(O)—, —S(O)₂—, —S(O)(NH)—, —NR⁵— or —C(R⁶)₂—;

R⁵ is H or optionally substituted C₁-C₆ alkyl;

each R⁶ is independently H, halo, or optionally substituted C₁-C₆ alkyl,or two R⁶ together with the carbon atom to which they are attached, forma C₁-C₆ alken-1-yl, optionally substituted cycloalkyl or optionallysubstituted heterocyclyl ring;

R³ and R⁴ are independently H, halo, or optionally substituted C₁-C₆alkyl, or R³ and R⁴ together with the carbon atoms to which they areattached, form an optionally substituted cycloalkyl or optionallysubstituted heterocyclyl ring, or R³ and R⁶ together with the carbonatoms to which they are attached, form an optionally substitutedcycloalkyl or optionally substituted heterocyclyl ring;

A is an optionally substituted cycloalkyl, optionally substitutedheterocyclyl, optionally substituted aryl or optionally substitutedheteroaryl ring;

L is absent, —O—, —S—, —S(O)—, —S(O)₂—, —NR⁷— or —C(R⁸)₂—;

R⁷ is H or optionally substituted C₁-C₆ alkyl;

each R⁸ is independently H, halo, or optionally substituted C₁-C₆ alkyl,or two R⁸ together with the carbon atom to which they are attached, forma optionally substituted cycloalkyl or optionally substitutedheterocyclyl ring;

R⁹ is optionally substituted cycloalkyl, optionally substitutedheterocyclyl, optionally substituted aryl or optionally substitutedheteroaryl; and

each R¹⁰ is independently cyano, halo or optionally substituted alkyl;

provided that at least one of the following occurs:

(1) at least one of R³ and R⁴ are halo or optionally substituted C₁-C₆alkyl, or R³ and R⁴ together with the carbon atoms to which they areattached, form an optionally substituted cycloalkyl or optionallysubstituted heterocyclyl ring, or R³ and R⁶ together with the carbonatoms to which they are attached, form a optionally substitutedcycloalkyl or optionally substituted heterocyclyl ring;

(2) L is absent or —C(R⁸)₂—, and each R⁸ is optionally substituted C₁-C₆alkyl or halo, or two R⁸ together with the carbon atom to which they areattached, form an optionally substituted cycloalkyl or optionallysubstituted heterocyclyl ring;

(3) Y² is —C(R⁶)₂—; and one R⁶ is hydrogen, halo, or optionallysubstituted C₁-C₆ alkyl, and the other R⁶ is halo or optionallysubstituted C₁-C₆ alkyl; or two R⁶ together with the carbon atom towhich they are attached, form a C₁-C₆ alken-1-yl, optionally substitutedcycloalkyl or optionally substituted heterocyclyl ring;

(4) Y² is —O—; and A is substituted with halo or cyano; or A isthiazolyl or a 3- or 4-membered ring;

(5) Y² is —S—, —S(O)—, or —S(O)₂—; and A is other than isoxazole or Y²is —S(O)(NH)—;

(6) Y² is —NR⁵—; X⁶, X⁷, X⁸ and X⁹ together form an optionallysubstituted phenyl, and A is other than isoxazole, pyrazole andtriazole; X⁶, X⁷, X⁸ and X⁹ together form an optionally substitutedpyridyl, and A is other than triazole; or X⁶, X⁷, X⁸ and X⁹ areoptionally substituted pyrimidyl, and A is other than pyrazole andtriazole; or

(7) Y² is —O—; X¹ and X² together form an optionally substitutedpyridyl, and A is other than isoxazole;

(8) R¹ is C₂-C₆ alkyl optionally substituted with halo, hydroxy orcyano; or

(9) when X¹ and X² form an optionally substituted phenyl ring as in themoiety

at least one substituent is at the 1 or 4 position and is (a) other thanfluoro, chloro or methyl at the 1 position, and/or (b) other than fluoroor methyl for the 4 position;

and with the further proviso that the compound is not:5-(difluoro(phenyl)methyl)-N-(4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)isoxazole-3-carboxamide;5-(difluoro(phenyl)methyl)-N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)isoxazole-3-carboxamide;2-(4-bromobenzyl)-N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)thiazole-4-carboxamide;2-benzyl-N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)thiazole-4-carboxamide;4-(1,4-dihydro-2-oxo-3(2H)-quinazolinyl)-N-[2,3,4,5-tetrahydro-1-(1-methylethyl)-2-oxo-1H-1-benzazepin-3-yl]-1-piperidinecarboxamide;4-(2-amino-7-chloro-4-quinolinyl)-N-[(3S)-2,3,4,5-tetrahydro-2-oxo-1H-1-benzazepin-3-yl]-1-piperazinecarboxamide;or4-(2-amino-7-chloro-4-quinolinyl)-N-[(3S)-2,3,4,5-tetrahydro-1-methyl-2-oxo-1H-1-benzazepin-3-yl]-1-piperazinecarboxamide.

In certain embodiments, the compound is of Formula II wherein

q is 0, 1, or 2;

X⁶, X⁷, X⁸ and X⁹ are each N or CH;

R¹ is H or optionally substituted C₁-C₆ alkyl;

Y² is —O—, —S—, —S(O)—, —S(O)₂—, —S(O)(NH)—, —NR⁵— or —C(R⁶)₂—;

R⁵ is H or optionally substituted C₁-C₆ alkyl;

each R⁶ is independently H, halo, optionally substituted C₁-C₆ alkyl, ortwo R⁶ together with the carbon atom to which they are attached, form aC₁-C₆ alken-1-yl, optionally substituted cycloalkyl or optionallysubstituted heterocyclyl ring;

R³ and R⁴ are independently H, halo, optionally substituted C₁-C₆ alkyl,R³ and R⁴ together with the carbon atoms to which they are attached,form an optionally substituted cycloalkyl or optionally substitutedheterocyclyl ring, or R³ and R⁶ together with the carbon atoms to whichthey are attached, form an optionally substituted cycloalkyl oroptionally substituted heterocyclyl ring;

A is an optionally substituted cycloalkyl, optionally substitutedheterocyclyl ring or optionally substituted heteroaryl ring;

L is absent, —O—, —S—, —S(O)—, —S(O)₂—, —NR⁷— or —C(R⁸)₂—;

R⁷ is H or optionally substituted C₁-C₆ alkyl;

each R⁸ is independently H, halo, optionally substituted C₁-C₆ alkyl, ortwo R⁸ together with the carbon atom to which they are attached, form aoptionally substituted cycloalkyl or optionally substituted heterocyclylring;

R⁹ is optionally substituted cycloalkyl, optionally substitutedheterocyclyl, optionally substituted aryl or optionally substitutedheteroaryl; and

each R¹⁰ is independently halo or optionally substituted alkyl;

provided that at least one of the following occurs:

(1) at least one of R³ and R⁴ are halo or optionally substituted C₁-C₆alkyl, R³ and R⁴ together with the carbon atoms to which they areattached, form an optionally substituted cycloalkyl or optionallysubstituted heterocyclyl ring, or R³ and R⁶ together with the carbonatoms to which they are attached, form a optionally substitutedcycloalkyl or optionally substituted heterocyclyl ring;

(2) L is absent or —C(R⁸)₂—, and each R⁸ is optionally substituted C₁-C₆alkyl or halo provided that the compound is not5-(difluoro(phenyl)methyl)-N-(4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)isoxazole-3-carboxamideor not5-(difluoro(phenyl)methyl)-N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)isoxazole-3-carboxamideor two R⁸ together with the carbon atom to which they are attached, forman optionally substituted cycloalkyl or optionally substitutedheterocyclyl ring;

(3) Y² is —C(R⁶)₂—; and one R⁶ is hydrogen, halo, or optionallysubstituted C₁-C₆ alkyl, and the other R⁶ is halo or optionallysubstituted C₁-C₆ alkyl; or two R⁶ together with the carbon atom towhich they are attached, form a C₁-C₆ alken-1-yl, optionally substitutedcycloalkyl or optionally substituted heterocyclyl ring;

(4) Y² is —O—; and A is substituted with halo or cyano; or A isthiazolyl or a 3- or 4-membered ring; provided that the compound is not2-(4-bromobenzyl)-N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)thiazole-4-carboxamideor2-benzyl-N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)thiazole-4-carboxamide;

(5) Y² is —S—, —S(O)—, or —S(O)₂—; and A is other than 1,3-isoxazole orY² is —S(O)N(H)—;

(6) Y² is —NR⁵—; X⁶, X⁷, X⁸ and X⁹ together form an optionallysubstituted phenyl, and A is other than isoxazole, pyrazole andtriazole; X⁶, X⁷, X⁸ and X⁹ together form an optionally substitutedpyridyl, and A is other than triazole; or X⁶, X⁷, X⁸ and X⁹ areoptionally substituted pyrimidyl, and A is other than pyrazole andtriazole; or

or a pharmaceutically acceptable salt, prodrug, tautomer, stereoisomeror mixture of stereoisomers thereof.

In certain embodiments, the compound is of Formula II and L is absent or—C(R⁸)₂—, and two R together with the carbon atom to which they areattached, form an optionally substituted cycloalkyl or optionallysubstituted heterocyclyl ring.

In any of the embodiments of Formula II (or subformula thereof), R¹ is Hor optionally substituted C₁-C₆ alkyl. In any of the embodiments ofFormula II (or subformula thereof), R¹ is H or C₁-C₆ alkyl.

In any of the embodiments of Formula II (or subformula thereof), q is 0,1 or 2 and when present, each R¹⁰ is independently cyano, halo,optionally substituted C₁-C₆ alkyl or —S(O)₂—C₁-C₆ alkyl. In any of theembodiments of Formula II (or subformula thereof), q is 0, 1 or 2 andwhen present, each R¹ is independently cyano, halo or optionallysubstituted alkyl. In any of the embodiments of Formula II (orsubformula thereof), each R¹⁰ is independently halo. In certainembodiments, each R¹⁰ is independently fluoro. In any of the embodimentsof Formula II (or subformula thereof), q is 0. In any of the embodimentsof Formula II (or subformula thereof), q is 1. In any of the embodimentsof Formula II (or subformula thereof), q is 2.

In certain embodiments, the compound is of Formula IIa:

or a pharmaceutically acceptable salt, prodrug, tautomer, stereoisomeror mixture of stereoisomers thereof;

wherein

q is 0, 1 or 2;

R¹ is H or C₁-C₆ alkyl optionally substituted with halo, hydroxy orcyano;

Y² is —O—, —S—, —S(O)—, —S(O)₂—, —S(O)(NH)—, —NR⁵— or —C(R⁶)₂—;

R⁵ is H or optionally substituted C₁-C₆ alkyl;

each R⁶ is independently H, halo, or optionally substituted C₁-C₆ alkyl,or two R⁶ together with the carbon atom to which they are attached, forma C₁-C₆ alken-1-yl, optionally substituted cycloalkyl or optionallysubstituted heterocyclyl ring;

R³ and R⁴ are independently H, halo, or optionally substituted C₁-C₆alkyl, or R³ and R⁴ together with the carbon atoms to which they areattached, form an optionally substituted cycloalkyl or heterocyclylring, or R³ and R⁶ together with the carbon atoms to which they areattached, form an optionally substituted cycloalkyl or optionallysubstituted heterocyclyl ring;

A is an optionally substituted cycloalkyl, optionally substitutedheterocyclyl, optionally substituted aryl or optionally substitutedheteroaryl ring;

L is absent, —O—, —S—, —S(O)—, —S(O)₂—, —NR⁷— or —C(R⁸)₂—;

R⁷ is H or optionally substituted C₁-C₆ alkyl;

each R⁸ is independently H, halo, or optionally substituted C₁-C₆ alkyl,or two R⁸ together with the carbon atom to which they are attached, forma optionally substituted cycloalkyl or heterocyclyl ring;

R⁹ is optionally substituted cycloalkyl, optionally substitutedheterocyclyl, optionally substituted aryl or optionally substitutedheteroaryl; and

each R¹⁰ is independently cyano, halo or optionally substituted alkyl;

provided that at least one of the following occurs:

(1) at least one of R³ and R⁴ are halo or optionally substituted C₁-C₆alkyl, R³ and R⁴ together with the carbon atoms to which they areattached, form an optionally substituted cycloalkyl or optionallysubstituted heterocyclyl ring, or R³ and R⁶ together with the carbonatoms to which they are attached, form a optionally substitutedcycloalkyl or optionally substituted heterocyclyl ring;

(2) L is absent or —C(R⁸)₂—, and two R⁸ together with the carbon atom towhich they are attached, form an optionally substituted cycloalkyl oroptionally substituted heterocyclyl ring;

(3) Y² is —C(R⁶)₂—; and two R⁶ together with the carbon atom to whichthey are attached, form a C₁-C₆ alken-1-yl, optionally substitutedcycloalkyl or optionally substituted heterocyclyl ring;

(4) R¹ is C₂-C₆ alkyl optionally substituted with halo, hydroxy orcyano; or

(5) when X¹ and X² form an optionally substituted phenyl ring as in themoiety

at least one substituent is at the 1 or 4 position and is (a) other thanfluoro, chloro or methyl at the 1 position, and/or (b) other than fluoroor methyl for the 4 position;

and with the further proviso that the compound is not:5-(difluoro(phenyl)methyl)-N-(4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)isoxazole-3-carboxamide;5-(difluoro(phenyl)methyl)-N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)isoxazole-3-carboxamide;2-(4-bromobenzyl)-N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)thiazole-4-carboxamide;2-benzyl-N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)thiazole-4-carboxamide;4-(1,4-dihydro-2-oxo-3(2H)-quinazolinyl)-N-[2,3,4,5-tetrahydro-1-(1-methylethyl)-2-oxo-1H-1-benzazepin-3-yl]-1-piperidinecarboxamide;4-(2-amino-7-chloro-4-quinolinyl)-N-[(3S)-2,3,4,5-tetrahydro-2-oxo-1H-1-benzazepin-3-yl]-1-piperazinecarboxamide;or4-(2-amino-7-chloro-4-quinolinyl)-N-[(3S)-2,3,4,5-tetrahydro-1-methyl-2-oxo-1H-1-benzazepin-3-yl]-1-piperazinecarboxamide.

In certain embodiments, the compound is of Formula IIa wherein

R¹ is H or optionally substituted C₁-C₆ alkyl;

Y² is —O—, —S—, —S(O)—, —S(O)₂—, —S(O)(NH)—, —NR⁵— or —C(R⁶)₂—;

R⁵ is H or optionally substituted C₁-C₆ alkyl;

each R⁶ is independently H, halo, optionally substituted C₁-C₆ alkyl, ortwo R⁶ together with the carbon atom to which they are attached, form aC₁-C₆ alken-1-yl, optionally substituted cycloalkyl or optionallysubstituted heterocyclyl ring;

R³ and R⁴ are independently H, halo, optionally substituted C₁-C₆ alkyl,R³ and R⁴ together with the carbon atoms to which they are attached,form an optionally substituted cycloalkyl or heterocyclyl ring, or R³and R⁶ together with the carbon atoms to which they are attached, forman optionally substituted cycloalkyl or optionally substitutedheterocyclyl ring;

A is an optionally substituted cycloalkyl, optionally substitutedheterocyclyl ring or optionally substituted heteroaryl ring;

L is absent, —O—, —S—, —S(O)—, —S(O)₂—, —NR⁷— or —C(R⁸)₂—;

R⁷ is H or optionally substituted C₁-C₆ alkyl;

each R⁸ is independently H, halo, optionally substituted C₁-C₆ alkyl, ortwo R⁸ together with the carbon atom to which they are attached, form aoptionally substituted cycloalkyl or heterocyclyl ring; and

R⁹ is optionally substituted cycloalkyl, optionally substitutedheterocyclyl, optionally substituted aryl or optionally substitutedheteroaryl;

provided that at least one of the following occurs:

(1) at least one of R³ and R⁴ are halo or optionally substituted C₁-C₆alkyl, R³ and R⁴ together with the carbon atoms to which they areattached, form an optionally substituted cycloalkyl or optionallysubstituted heterocyclyl ring, or R³ and R⁶ together with the carbonatoms to which they are attached, form a optionally substitutedcycloalkyl or optionally substituted heterocyclyl ring;

(2) L is absent or —C(R⁸)₂—, and two R⁸ together with the carbon atom towhich they are attached, form an optionally substituted cycloalkyl oroptionally substituted heterocyclyl ring; or

(3) Y² is —C(R⁶)₂—; and two R⁶ together with the carbon atom to whichthey are attached, form a C₁-C₆ alken-1-yl, optionally substitutedcycloalkyl or optionally substituted heterocyclyl ring;

or a pharmaceutically acceptable salt, prodrug, tautomer, stereoisomeror mixture of stereoisomers thereof.

In certain embodiments, the compound is of Formula IIa-1:

wherein one of R¹¹ or R¹² is halo and the other is C₁₋₆alkyl or C₁₋₆cycloalkyl and the remaining variables are as defined throughout.

In certain embodiments, the compound is of Formula IIa-2:

or a pharmaceutically acceptable salt, prodrug, tautomer, stereoisomeror mixture of stereoisomers thereof;

wherein

q is 0, 1 or 2;

R¹ is H or C₁-C₆ alkyl optionally substituted with halo, hydroxy orcyano;

R⁴ is H, halo, or optionally substituted C₁-C₆ alkyl;

A is an optionally substituted cycloalkyl, optionally substitutedheterocyclyl, optionally substituted aryl or optionally substitutedheteroaryl ring;

L is absent, —O—, —S—, —S(O)—, —S(O)₂—, —NR⁷— or —C(R⁸)₂—;

R⁷ is H or optionally substituted C₁-C₆ alkyl;

each R⁸ is independently H, halo, or optionally substituted C₁-C₆ alkyl,or two R⁸ together with the carbon atom to which they are attached, forma optionally substituted cycloalkyl or heterocyclyl ring;

R⁹ is optionally substituted cycloalkyl, optionally substitutedheterocyclyl, optionally substituted aryl or optionally substitutedheteroaryl; and

each R¹⁰ is independently cyano, halo or optionally substituted alkyl.

In certain embodiments, the compound is of Formula IIa-2a. In certainembodiments, the compound is of Formula IIa-2b. In certain embodiments,the compound is of Formula IIa-3. In certain embodiments, the compoundis of Formula IIa-4. In certain embodiments, the compound is of FormulaIIa-5.

In certain embodiments, the compound is of Formula IIb:

or a pharmaceutically acceptable salt, prodrug, tautomer, stereoisomeror mixture of stereoisomers thereof;

wherein

q is 0, 1 or 2;

R¹ is H or C₁-C₆ alkyl optionally substituted with halo, hydroxy orcyano;

Y² is —O—, —S—, —S(O)—, —S(O)₂—, —S(O)(NH)—, —NR⁵— or —C(R⁶)₂—;

R⁵ is H or optionally substituted C₁-C₆ alkyl;

each R⁶ is independently H, halo, or optionally substituted C₁-C₆ alkyl,or two R⁶ together with the carbon atom to which they are attached, forma C₁-C₆ alken-1-yl, optionally substituted cycloalkyl or optionallysubstituted heterocyclyl ring;

R³ and R⁴ are independently H, halo, or optionally substituted C₁-C₆alkyl, or R³ and R⁴ together with the carbon atoms to which they areattached, form an optionally substituted cycloalkyl or optionallysubstituted heterocyclyl ring, or R³ and R⁶ together with the carbonatoms to which they are attached, form an optionally substitutedcycloalkyl or optionally substituted heterocyclyl ring;

A is an optionally substituted cycloalkyl, optionally substitutedheterocyclyl, optionally substituted aryl or optionally substitutedheteroaryl ring;

L is absent, —O—, —S—, —S(O)—, —S(O)₂—, —NR⁷— or —C(R⁸)₂—;

R⁷ is H or optionally substituted C₁-C₆ alkyl;

each R⁸ is independently H, halo, or optionally substituted C₁-C₆ alkyl,or two R⁸ together with the carbon atom to which they are attached, forma optionally substituted cycloalkyl or optionally substitutedheterocyclyl ring;

R⁹ is optionally substituted cycloalkyl, optionally substitutedheterocyclyl, optionally substituted aryl or optionally substitutedheteroaryl; and

each R¹⁰ is independently cyano, halo or optionally substituted alkyl;

provided that at least one of the following occurs:

(1) at least one of R³ and R⁴ are halo or optionally substituted C₁-C₆alkyl, or R³ and R⁴ together with the carbon atoms to which they areattached, form an optionally substituted cycloalkyl or optionallysubstituted heterocyclyl ring, or R³ and R⁶ together with the carbonatoms to which they are attached, form a optionally substitutedcycloalkyl or optionally substituted heterocyclyl ring;

(2) L is absent or —C(R⁸)₂—, and two R⁸ together with the carbon atom towhich they are attached, form an optionally substituted cycloalkyl oroptionally substituted heterocyclyl ring;

(3) Y² is —C(R⁶)₂—; and two R⁶ together with the carbon atom to whichthey are attached, form a C₁-C₆ alken-1-yl, optionally substitutedcycloalkyl or optionally substituted heterocyclyl ring; or

(4) the compound is not5-(phenylmethyl)-N-[(3S)-1,2,3,4-tetrahydro-7-methyl-2-oxopyrido[2,3-b][1,4]oxazepin-3-yl]-3-isoxazolecarboxamide;N-[(3S)-8-fluoro-2,3,4,5-tetrahydro-1-methyl-2-oxo-1H-pyrido[2,3-b][1,4]diazepin-3-yl]-3-(phenylmethyl)-1H-1,2,4-triazole-5-carboxamide;5-(phenylmethyl)-N-[(3S)-1,2,3,4-tetrahydro-7-methyl-2-oxopyrido[2,3-b][1,4]oxazepin-3-yl]-3-isoxazolecarboxamide;orN-[(3S)-8-fluoro-2,3,4,5-tetrahydro-1-methyl-2-oxo-1H-pyrido[2,3-b][1,4]diazepin-3-yl]-3-(phenylmethyl)-1H-1,2,4-triazole-5-carboxamide.

In certain embodiments, the compound is of Formula IIb wherein

R¹ is H or optionally substituted C₁-C₆ alkyl;

Y² is —O—, —S—, —S(O)—, —S(O)₂—, —S(O)(NH)—, —NR⁵— or —C(R⁶)₂—;

R⁵ is H or optionally substituted C₁-C₆ alkyl;

each R⁶ is independently H, halo, or optionally substituted C₁-C₆ alkyl,or two R⁶ together with the carbon atom to which they are attached, forma C₁-C₆ alken-1-yl, optionally substituted cycloalkyl or optionallysubstituted heterocyclyl ring;

R³ and R⁴ are independently H, halo, or optionally substituted C₁-C₆alkyl, or R³ and R⁴ together with the carbon atoms to which they areattached, form an optionally substituted cycloalkyl or optionallysubstituted heterocyclyl ring, or R³ and R⁶ together with the carbonatoms to which they are attached, form an optionally substitutedcycloalkyl or optionally substituted heterocyclyl ring;

A is an optionally substituted cycloalkyl, optionally substitutedheterocyclyl ring or optionally substituted heteroaryl ring;

L is absent, —O—, —S—, —S(O)—, —S(O)₂—, —NR⁷— or —C(R⁸)₂—;

R⁷ is H or optionally substituted C₁-C₆ alkyl;

each R⁸ is independently H, halo, or optionally substituted C₁-C₆ alkyl,or two R⁸ together with the carbon atom to which they are attached, forma optionally substituted cycloalkyl or optionally substitutedheterocyclyl ring; and

R⁹ is optionally substituted cycloalkyl, optionally substitutedheterocyclyl, optionally substituted aryl or optionally substitutedheteroaryl;

provided that at least one of the following occurs:

(1) at least one of R³ and R⁴ are halo or optionally substituted C₁-C₆alkyl, or R³ and R⁴ together with the carbon atoms to which they areattached, form an optionally substituted cycloalkyl or optionallysubstituted heterocyclyl ring, or R³ and R⁶ together with the carbonatoms to which they are attached, form a optionally substitutedcycloalkyl or optionally substituted heterocyclyl ring;

(2) L is absent or —C(R⁸)₂—, and two R⁸ together with the carbon atom towhich they are attached, form an optionally substituted cycloalkyl oroptionally substituted heterocyclyl ring; or

(3) Y² is —C(R⁶)₂—; and two R⁶ together with the carbon atom to whichthey are attached, form a C₁-C₆ alken-1-yl, optionally substitutedcycloalkyl or optionally substituted heterocyclyl ring;

or a pharmaceutically acceptable salt, prodrug, tautomer, stereoisomeror mixture of stereoisomers thereof.

In certain embodiments, the compound is of Formula IIb-1:

or a pharmaceutically acceptable salt, prodrug, tautomer, stereoisomeror mixture of stereoisomers thereof;

wherein

q is 0, 1 or 2;

R¹ is H or C₁-C₆ alkyl optionally substituted with halo, hydroxy orcyano;

R⁴ is H, halo, or optionally substituted C₁-C₆ alkyl;

A is an optionally substituted cycloalkyl, optionally substitutedheterocyclyl, optionally substituted aryl or optionally substitutedheteroaryl ring;

L is absent, —O—, —S—, —S(O)—, —S(O)₂—, —NR⁷— or —C(R⁸)₂—;

R⁷ is H or optionally substituted C₁-C₆ alkyl;

each R⁸ is independently H, halo, or optionally substituted C₁-C₆ alkyl,or two R⁸ together with the carbon atom to which they are attached, forma optionally substituted cycloalkyl or heterocyclyl ring;

R⁹ is optionally substituted cycloalkyl, optionally substitutedheterocyclyl, optionally substituted aryl or optionally substitutedheteroaryl; and

each R¹⁰ is independently cyano, halo or optionally substituted alkyl.

In certain embodiments, the compound is of Formula IIb-2. In certainembodiments, the compound is of Formula IIb-3. In certain embodiments,the compound is of Formula IIb-4. In certain embodiments, the compoundis of Formula IIb-5. In certain embodiments, the compound is of FormulaIIb-6.

In certain embodiments, the compound is of Formula IIc:

or a pharmaceutically acceptable salt, prodrug, tautomer, stereoisomeror mixture of stereoisomers thereof;

wherein

q is 0, 1 or 2;

R¹ is H or C₁-C₆ alkyl optionally substituted with halo, hydroxy orcyano;

Y² is —O—, —S—, —S(O)—, —S(O)₂—, —S(O)(NH)—, —NR⁵— or —C(R⁶)₂—;

R⁵ is H or optionally substituted C₁-C₆ alkyl;

each R⁶ is independently H, halo, or optionally substituted C₁-C₆ alkyl,or two R⁶ together with the carbon atom to which they are attached, forma C₁-C₆ alken-1-yl, optionally substituted cycloalkyl or optionallysubstituted heterocyclyl ring;

R³ and R⁴ are independently H, halo, or optionally substituted C₁-C₆alkyl, or R³ and R⁴ together with the carbon atoms to which they areattached, form an optionally substituted cycloalkyl or optionallysubstituted heterocyclyl ring, or R³ and R⁶ together with the carbonatoms to which they are attached, form an optionally substitutedcycloalkyl or optionally substituted heterocyclyl ring;

A is an optionally substituted cycloalkyl, optionally substitutedheterocyclyl ring, optionally substituted aryl or optionally substitutedheteroaryl ring;

L is absent, —O—, —S—, —S(O)—, —S(O)₂—, —NR⁷— or —C(R⁸)₂—;

R⁷ is H or optionally substituted C₁-C₆ alkyl;

each R⁸ is independently H, halo, or optionally substituted C₁-C₆ alkyl,or two R⁸ together with the carbon atom to which they are attached, forma optionally substituted cycloalkyl or optionally substitutedheterocyclyl ring;

R⁹ is optionally substituted cycloalkyl, optionally substitutedheterocyclyl, optionally substituted aryl or optionally substitutedheteroaryl; and

each R¹⁰ is independently cyano, halo or optionally substituted alkyl.

In certain embodiments, the compound is of Formula IIc wherein

R¹ is H or optionally substituted C₁-C₆ alkyl;

Y² is —O—, —S—, —S(O)—, —S(O)₂—, —S(O)(NH)—, —NR⁵— or —C(R⁶)₂—;

R⁵ is H or optionally substituted C₁-C₆ alkyl;

each R⁶ is independently H, halo, optionally substituted C₁-C₆ alkyl, ortwo R⁶ together with the carbon atom to which they are attached, form aC₁-C₆ alken-1-yl, optionally substituted cycloalkyl or optionallysubstituted heterocyclyl ring;

R³ and R⁴ are independently H, halo, optionally substituted C₁-C₆ alkyl,R³ and R⁴ together with the carbon atoms to which they are attached,form an optionally substituted cycloalkyl or optionally substitutedheterocyclyl ring, or R³ and R⁶ together with the carbon atoms to whichthey are attached, form an optionally substituted cycloalkyl oroptionally substituted heterocyclyl ring;

A is an optionally substituted cycloalkyl, optionally substitutedheterocyclyl ring or optionally substituted heteroaryl ring;

L is absent, —O—, —S—, —S(O)—, —S(O)₂—, —NR⁷— or —C(R⁸)₂—;

R⁷ is H or optionally substituted C₁-C₆ alkyl;

each R⁸ is independently H, halo, optionally substituted C₁-C₆ alkyl, ortwo R⁸ together with the carbon atom to which they are attached, form aoptionally substituted cycloalkyl or optionally substituted heterocyclylring; and

R⁹ is optionally substituted cycloalkyl, optionally substitutedheterocyclyl, optionally substituted aryl or optionally substitutedheteroaryl;

provided that at least one of the following occurs:

(1) at least one of R³ and R⁴ are halo or optionally substituted C₁-C₆alkyl, R³ and R⁴ together with the carbon atoms to which they areattached, form an optionally substituted cycloalkyl or optionallysubstituted heterocyclyl ring, or R³ and R⁶ together with the carbonatoms to which they are attached, form a optionally substitutedcycloalkyl or optionally substituted heterocyclyl ring;

(2) L is absent or —C(R⁸)₂—, and two R⁸ together with the carbon atom towhich they are attached, form an optionally substituted cycloalkyl oroptionally substituted heterocyclyl ring; or

(3) Y² is —C(R⁶)₂—; and two R⁶ together with the carbon atom to whichthey are attached, form a C₁-C₆ alken-1-yl, optionally substitutedcycloalkyl or optionally substituted heterocyclyl ring;

or a pharmaceutically acceptable salt, prodrug, tautomer, stereoisomeror mixture of stereoisomers thereof.

In certain embodiments, provided is a compound of Formula IIc or apharmaceutically acceptable salt, prodrug, tautomer, stereoisomer ormixture of stereoisomers thereof;

wherein

q is 0, 1 or 2;

R¹ is H or C₁-C₆ alkyl;

Y² is —O— or —C(R⁶)₂—;

each R⁶ is independently H, halo, or optionally substituted C₁-C₆ alkyl,or two R⁶ together with the carbon atom to which they are attached, forma C₁-C₆ alken-1-yl, optionally substituted cycloalkyl or optionallysubstituted heterocyclyl ring;

R³ and R⁴ are independently H, halo, or optionally substituted C₁-C₆alkyl, or R³ and R⁴ together with the carbon atoms to which they areattached, form an optionally substituted cycloalkyl or optionallysubstituted heterocyclyl ring, or R³ and R⁶ together with the carbonatoms to which they are attached, form an optionally substitutedcycloalkyl or optionally substituted heterocyclyl ring;

A is an optionally substituted cycloalkyl, optionally substitutedheterocyclyl, optionally substituted aryl or optionally substitutedheteroaryl ring;

L is absent, —O— or —C(R⁸)₂—;

each R⁸ is independently H, halo, or optionally substituted C₁-C₆ alkyl,or two R⁸ together with the carbon atom to which they are attached, forma optionally substituted cycloalkyl or optionally substitutedheterocyclyl ring;

R⁹ is optionally substituted cycloalkyl, optionally substitutedheterocyclyl, optionally substituted aryl or optionally substitutedheteroaryl; and

each R¹⁰ is independently cyano, halo, optionally substituted C₁-C₆alkyl or —S(O)₂—C₁-C₆ alkyl.

In certain embodiments, the compound is of Formula IIc-1:

or a pharmaceutically acceptable salt, prodrug, tautomer, stereoisomeror mixture of stereoisomers thereof;

wherein

q is 0, 1 or 2;

R¹ is H or C₁-C₆ alkyl optionally substituted with halo, hydroxy orcyano;

R⁴ is H, halo, or optionally substituted C₁-C₆ alkyl;

A is an optionally substituted cycloalkyl, optionally substitutedheterocyclyl, optionally substituted aryl or optionally substitutedheteroaryl ring;

L is absent, —O—, —S—, —S(O)—, —S(O)₂—, —NR⁷— or —C(R⁸)₂—;

R⁷ is H or optionally substituted C₁-C₆ alkyl;

each R⁸ is independently H, halo, or optionally substituted C₁-C₆ alkyl,or two R⁸ together with the carbon atom to which they are attached, forma optionally substituted cycloalkyl or heterocyclyl ring;

R⁹ is optionally substituted cycloalkyl, optionally substitutedheterocyclyl, optionally substituted aryl or optionally substitutedheteroaryl; and

each R¹⁰ is independently cyano, halo or optionally substituted alkyl.

In certain embodiments, the compound is of Formula IIc-2. In certainembodiments, the compound is of Formula IIc-3. In certain embodiments,the compound is of Formula IIc-4. In certain embodiments, the compoundis of Formula IIc-5. In certain embodiments, the compound is of FormulaIIc-6.

In certain embodiments, provided is a compound of Formula IIc-4:

or a pharmaceutically acceptable salt, prodrug, tautomer, stereoisomeror mixture of stereoisomers thereof;

wherein

q is 0, 1 or 2;

R¹ is H or C₁-C₆ alkyl;

Y² is —O— or —C(R⁶)₂—;

each R⁶ is independently H, halo, or optionally substituted C₁-C₆ alkyl,or two R⁶ together with the carbon atom to which they are attached, forma C₁-C₆ alken-1-yl, optionally substituted cycloalkyl or optionallysubstituted heterocyclyl ring;

R³ and R⁴ are independently H, halo, or optionally substituted C₁-C₆alkyl, or R³ and R⁴ together with the carbon atoms to which they areattached, form an optionally substituted cycloalkyl or optionallysubstituted heterocyclyl ring, or R³ and R⁶ together with the carbonatoms to which they are attached, form an optionally substitutedcycloalkyl or optionally substituted heterocyclyl ring;

A is an optionally substituted cycloalkyl, optionally substitutedheterocyclyl, optionally substituted aryl or optionally substitutedheteroaryl ring;

L is absent, —O— or —C(R⁸)₂—;

each R⁸ is independently H, halo, or optionally substituted C₁-C₆ alkyl,or two R⁸ together with the carbon atom to which they are attached, forma optionally substituted cycloalkyl or optionally substitutedheterocyclyl ring;

R⁹ is optionally substituted cycloalkyl, optionally substitutedheterocyclyl, optionally substituted aryl or optionally substitutedheteroaryl; and

each R¹⁰ is independently cyano, halo, optionally substituted C₁-C₆alkyl or —S(O)₂—C₁-C₆ alkyl.

In certain embodiments, the compound is of Formula IId:

or a pharmaceutically acceptable salt, prodrug, tautomer, stereoisomeror mixture of stereoisomers thereof;

wherein

q is 0, 1 or 2;

R¹ is H or C₁-C₆ alkyl optionally substituted with halo, hydroxy orcyano;

Y² is —O—, —S—, —S(O)—, —S(O)₂—, —S(O)(NH)—, —NR⁵— or —C(R⁶)₂—;

R⁵ is H or optionally substituted C₁-C₆ alkyl;

each R⁶ is independently H, halo, or optionally substituted C₁-C₆ alkyl,or two R⁶ together with the carbon atom to which they are attached, forma C₁-C₆ alken-1-yl, optionally substituted cycloalkyl or optionallysubstituted heterocyclyl ring;

R³ and R⁴ are independently H, halo, or optionally substituted C₁-C₆alkyl, or R³ and R⁴ together with the carbon atoms to which they areattached, form an optionally substituted cycloalkyl or optionallysubstituted heterocyclyl ring, or R³ and R⁶ together with the carbonatoms to which they are attached, form an optionally substitutedcycloalkyl or optionally substituted heterocyclyl ring;

A is an optionally substituted cycloalkyl, optionally substitutedheterocyclyl, optionally substituted aryl or optionally substitutedheteroaryl ring;

L is absent, —O—, —S—, —S(O)—, —S(O)₂—, —NR⁷— or —C(R⁸)₂—;

R⁷ is H or optionally substituted C₁-C₆ alkyl;

each R⁸ is independently H, halo, or optionally substituted C₁-C₆ alkyl,or two R⁸ together with the carbon atom to which they are attached, forma optionally substituted cycloalkyl or optionally substitutedheterocyclyl ring;

R⁹ is optionally substituted cycloalkyl, optionally substitutedheterocyclyl, optionally substituted aryl or optionally substitutedheteroaryl; and

each R¹⁰ is independently cyano, halo or optionally substituted alkyl;

provided that at least one of the following occurs:

(1) at least one of R³ and R⁴ are halo or optionally substituted C₁-C₆alkyl, or R³ and R⁴ together with the carbon atoms to which they areattached, form an optionally substituted cycloalkyl or optionallysubstituted heterocyclyl ring, or R³ and R⁶ together with the carbonatoms to which they are attached, form a optionally substitutedcycloalkyl or optionally substituted heterocyclyl ring;

(2) L is absent or —C(R⁸)₂—, and two R⁸ together with the carbon atom towhich they are attached, form an optionally substituted cycloalkyl oroptionally substituted heterocyclyl ring;

(3) Y² is —C(R⁶)₂—; and two R⁶ together with the carbon atom to whichthey are attached, form a C₁-C₆ alken-1-yl, optionally substitutedcycloalkyl or optionally substituted heterocyclyl ring; or

(4) the compound is not5-(phenylmethyl)-N-[(3S)-2,3,4,5-tetrahydro-4-oxopyrido[4,3-b][1,4]oxazepin-3-yl]-3-isoxazolecarboxamide;or

5-(phenylmethyl)-N-[(3S)-2,3,4,5-tetrahydro-4-oxopyrido[4,3-b][1,4]oxazepin-3-yl]-3-isoxazolecarboxamide.

In certain embodiments, the compound is of Formula IId wherein

R¹ is H or optionally substituted C₁-C₆ alkyl;

Y² is —O—, —S—, —S(O)—, —S(O)₂—, —S(O)(NH)—, —NR⁵— or —C(R⁶)₂—;

R⁵ is H or optionally substituted C₁-C₆ alkyl;

each R⁶ is independently H, halo, or optionally substituted C₁-C₆ alkyl,or two R⁶ together with the carbon atom to which they are attached, forma C₁-C₆ alken-1-yl, optionally substituted cycloalkyl or optionallysubstituted heterocyclyl ring;

R³ and R⁴ are independently H, halo, or optionally substituted C₁-C₆alkyl, or R³ and R⁴ together with the carbon atoms to which they areattached, form an optionally substituted cycloalkyl or optionallysubstituted heterocyclyl ring, or R³ and R⁶ together with the carbonatoms to which they are attached, form an optionally substitutedcycloalkyl or optionally substituted heterocyclyl ring;

A is an optionally substituted cycloalkyl, optionally substitutedheterocyclyl ring or optionally substituted heteroaryl ring;

L is absent, —O—, —S—, —S(O)—, —S(O)₂—, —NR⁷— or —C(R⁸)₂—;

R⁷ is H or optionally substituted C₁-C₆ alkyl;

each R⁸ is independently H, halo, or optionally substituted C₁-C₆ alkyl,or two R⁸ together with the carbon atom to which they are attached, forma optionally substituted cycloalkyl or optionally substitutedheterocyclyl ring; and

R⁹ is optionally substituted cycloalkyl, optionally substitutedheterocyclyl, optionally substituted aryl or optionally substitutedheteroaryl;

provided that at least one of the following occurs:

(1) at least one of R³ and R⁴ are halo or optionally substituted C₁-C₆alkyl, or R³ and R⁴ together with the carbon atoms to which they areattached, form an optionally substituted cycloalkyl or optionallysubstituted heterocyclyl ring, or R³ and R⁶ together with the carbonatoms to which they are attached, form a optionally substitutedcycloalkyl or optionally substituted heterocyclyl ring;

(2) L is absent or —C(R⁸)₂—, and two R⁸ together with the carbon atom towhich they are attached, form an optionally substituted cycloalkyl oroptionally substituted heterocyclyl ring; or

(3) Y² is —C(R⁶)₂—; and two R⁶ together with the carbon atom to whichthey are attached, form a C₁-C₆ alken-1-yl, optionally substitutedcycloalkyl or optionally substituted heterocyclyl ring;

or a pharmaceutically acceptable salt, prodrug, tautomer, stereoisomeror mixture of stereoisomers thereof.

In certain embodiments, the compound is of Formula IId-1:

or a pharmaceutically acceptable salt, prodrug, tautomer, stereoisomeror mixture of stereoisomers thereof;

wherein

q is 0, 1 or 2;

R¹ is H or C₁-C₆ alkyl optionally substituted with halo, hydroxy orcyano;

R⁴ is H, halo, or optionally substituted C₁-C₆ alkyl;

A is an optionally substituted cycloalkyl, optionally substitutedheterocyclyl, optionally substituted aryl or optionally substitutedheteroaryl ring;

L is absent, —O—, —S—, —S(O)—, —S(O)₂—, —NR⁷— or —C(R⁸)₂—;

R⁷ is H or optionally substituted C₁-C₆ alkyl;

each R⁸ is independently H, halo, or optionally substituted C₁-C₆ alkyl,or two R⁸ together with the carbon atom to which they are attached, forma optionally substituted cycloalkyl or heterocyclyl ring;

R⁹ is optionally substituted cycloalkyl, optionally substitutedheterocyclyl, optionally substituted aryl or optionally substitutedheteroaryl; and

each R¹⁰ is independently cyano, halo or optionally substituted alkyl.

In certain embodiments, the compound is of Formula IId-2. In certainembodiments, the compound is of Formula IId-3. In certain embodiments,the compound is of Formula IId-4. In certain embodiments, the compoundis of Formula IId-5. In certain embodiments, the compound is of FormulaIId-6.

In certain embodiments, provided is a compound of Formula IIe:

or a pharmaceutically acceptable salt, prodrug, tautomer, stereoisomeror mixture of stereoisomers thereof;

wherein

q is 0, 1 or 2;

R¹ is H or C₁-C₆ alkyl optionally substituted with halo, hydroxy orcyano;

Y² is —O—, —S—, —S(O)—, —S(O)₂—, —S(O)(NH)—, —NR₅— or —C(R⁶)₂—;

R⁵ is H or optionally substituted C₁-C₆ alkyl;

each R⁶ is independently H, halo, or optionally substituted C₁-C₆ alkyl,or two R⁶ together with the carbon atom to which they are attached, forma C₁-C₆ alken-1-yl, optionally substituted cycloalkyl or optionallysubstituted heterocyclyl ring;

R³ and R⁴ are independently H, halo, or optionally substituted C₁-C₆alkyl, or R³ and R⁴ together with the carbon atoms to which they areattached, form an optionally substituted cycloalkyl or optionallysubstituted heterocyclyl ring, or R³ and R⁶ together with the carbonatoms to which they are attached, form an optionally substitutedcycloalkyl or optionally substituted heterocyclyl ring;

A is an optionally substituted cycloalkyl, optionally substitutedheterocyclyl, optionally substituted aryl or optionally substitutedheteroaryl ring;

L is absent, —O—, —S—, —S(O)—, —S(O)₂—, —NR⁷— or —C(R⁸)₂—;

R⁷ is H or optionally substituted C₁-C₆ alkyl;

each R⁸ is independently H, halo, or optionally substituted C₁-C₆ alkyl,or two R⁸ together with the carbon atom to which they are attached, forma optionally substituted cycloalkyl or optionally substitutedheterocyclyl ring;

R⁹ is optionally substituted cycloalkyl, optionally substitutedheterocyclyl, optionally substituted aryl or optionally substitutedheteroaryl; and

each R¹⁰ is independently cyano, halo, optionally substituted C₁-C₆alkyl or —S(O)₂—C₁-C₆ alkyl.

In certain embodiments, the compound is of Formula IIe or apharmaceutically acceptable salt, prodrug, tautomer, stereoisomer ormixture of stereoisomers thereof;

wherein

q is 0, 1 or 2;

R¹ is H or C₁-C₆ alkyl optionally substituted with halo, hydroxy orcyano;

Y² is —O—, —S—, —S(O)—, —S(O)₂—, —S(O)(NH)—, —NR⁵— or —C(R⁶)₂—;

R⁵ is H or optionally substituted C₁-C₆ alkyl;

each R⁶ is independently H, halo, or optionally substituted C₁-C₆ alkyl,or two R⁶ together with the carbon atom to which they are attached, forma C₁-C₆ alken-1-yl, optionally substituted cycloalkyl or optionallysubstituted heterocyclyl ring;

R³ and R⁴ are independently H, halo, or optionally substituted C₁-C₆alkyl, or R³ and R⁴ together with the carbon atoms to which they areattached, form an optionally substituted cycloalkyl or optionallysubstituted heterocyclyl ring, or R³ and R⁶ together with the carbonatoms to which they are attached, form an optionally substitutedcycloalkyl or optionally substituted heterocyclyl ring;

A is an optionally substituted cycloalkyl, optionally substitutedheterocyclyl, optionally substituted aryl or optionally substitutedheteroaryl ring;

L is absent, —O—, —S—, —S(O)—, —S(O)₂—, —NR⁷— or —C(R⁸)₂—;

R⁷ is H or optionally substituted C₁-C₆ alkyl;

each R⁸ is independently H, halo, or optionally substituted C₁-C₆ alkyl,or two R⁸ together with the carbon atom to which they are attached, forma optionally substituted cycloalkyl or optionally substitutedheterocyclyl ring;

R⁹ is optionally substituted cycloalkyl, optionally substitutedheterocyclyl, optionally substituted aryl or optionally substitutedheteroaryl; and

each R¹⁰ is independently cyano, halo or optionally substituted alkyl.

In certain embodiments, the compound is of Formula IIe wherein

R¹ is H or optionally substituted C₁-C₆ alkyl;

Y² is —O—, —S—, —S(O)—, —S(O)₂—, —S(O)(NH)—, —NR⁵— or —C(R⁶)₂—;

R⁵ is H or optionally substituted C₁-C₆ alkyl;

each R⁶ is independently H, halo, optionally substituted C₁-C₆ alkyl, ortwo R⁶ together with the carbon atom to which they are attached, form aC₁-C₆ alken-1-yl, optionally substituted cycloalkyl or optionallysubstituted heterocyclyl ring;

R³ and R⁴ are independently H, halo, optionally substituted C₁-C₆ alkyl,R³ and R⁴ together with the carbon atoms to which they are attached,form an optionally substituted cycloalkyl or optionally substitutedheterocyclyl ring, or R³ and R⁶ together with the carbon atoms to whichthey are attached, form an optionally substituted cycloalkyl oroptionally substituted heterocyclyl ring;

A is an optionally substituted cycloalkyl, optionally substitutedheterocyclyl ring or optionally substituted heteroaryl ring;

L is absent, —O—, —S—, —S(O)—, —S(O)₂—, —NR⁷— or —C(R⁸)₂—;

R⁷ is H or optionally substituted C₁-C₆ alkyl;

each R⁸ is independently H, halo, optionally substituted C₁-C₆ alkyl, ortwo R⁸ together with the carbon atom to which they are attached, form aoptionally substituted cycloalkyl or optionally substituted heterocyclylring; and

R⁹ is optionally substituted cycloalkyl, optionally substitutedheterocyclyl, optionally substituted aryl or optionally substitutedheteroaryl; provided that at least one of the following occurs:

(1) at least one of R³ and R⁴ are halo or optionally substituted C₁-C₆alkyl, R³ and R⁴ together with the carbon atoms to which they areattached, form an optionally substituted cycloalkyl or optionallysubstituted heterocyclyl ring, or R³ and R⁶ together with the carbonatoms to which they are attached, form a optionally substitutedcycloalkyl or optionally substituted heterocyclyl ring;

(2) L is absent or —C(R⁸)₂—, and two R⁸ together with the carbon atom towhich they are attached, form an optionally substituted cycloalkyl oroptionally substituted heterocyclyl ring; or

(3) Y² is —C(R⁶)₂—; and two R⁶ together with the carbon atom to whichthey are attached, form a C₁-C₆ alken-1-yl, optionally substitutedcycloalkyl or optionally substituted heterocyclyl ring;

or a pharmaceutically acceptable salt, prodrug, tautomer, stereoisomeror mixture of stereoisomers thereof.

In certain embodiments, provided is a compound of Formula IIe or apharmaceutically acceptable salt, prodrug, tautomer, stereoisomer ormixture of stereoisomers thereof;

wherein

q is 0, 1 or 2;

R¹ is H or C₁-C₆ alkyl;

Y² is —O— or —C(R⁶)₂—;

each R⁶ is independently H, halo, or optionally substituted C₁-C₆ alkyl,or two R⁶ together with the carbon atom to which they are attached, forma C₁-C₆ alken-1-yl, optionally substituted cycloalkyl or optionallysubstituted heterocyclyl ring;

R³ and R⁴ are independently H, halo, or optionally substituted C₁-C₆alkyl, or R³ and R⁴ together with the carbon atoms to which they areattached, form an optionally substituted cycloalkyl or optionallysubstituted heterocyclyl ring, or R³ and R⁶ together with the carbonatoms to which they are attached, form an optionally substitutedcycloalkyl or optionally substituted heterocyclyl ring;

A is an optionally substituted cycloalkyl, optionally substitutedheterocyclyl, optionally substituted aryl or optionally substitutedheteroaryl ring;

L is absent, —O— or —C(R⁸)₂—;

each R⁸ is independently H, halo, or optionally substituted C₁-C₆ alkyl,or two R⁸ together with the carbon atom to which they are attached, forma optionally substituted cycloalkyl or optionally substitutedheterocyclyl ring;

R⁹ is optionally substituted cycloalkyl, optionally substitutedheterocyclyl, optionally substituted aryl or optionally substitutedheteroaryl; and

each R¹⁰ is independently cyano, halo, optionally substituted C₁-C₆alkyl or —S(O)₂—C₁-C₆ alkyl.

In certain embodiments, the compound is of Formula IIe-1:

wherein

or a pharmaceutically acceptable salt, prodrug, tautomer, stereoisomeror mixture of stereoisomers thereof;

q is 0, 1 or 2;

R¹ is H or C₁-C₆ alkyl optionally substituted with halo, hydroxy orcyano;

R⁴ is H, halo, or optionally substituted C₁-C₆ alkyl;

A is an optionally substituted cycloalkyl, optionally substitutedheterocyclyl, optionally substituted aryl or optionally substitutedheteroaryl ring;

L is absent, —O—, —S—, —S(O)—, —S(O)₂—, —NR⁷— or —C(R⁸)₂—;

R⁷ is H or optionally substituted C₁-C₆ alkyl;

each R⁸ is independently H, halo, or optionally substituted C₁-C₆ alkyl,or two R⁸ together with the carbon atom to which they are attached, forma optionally substituted cycloalkyl or heterocyclyl ring;

R⁹ is optionally substituted cycloalkyl, optionally substitutedheterocyclyl, optionally substituted aryl or optionally substitutedheteroaryl; and

each R¹⁰ is independently cyano, halo or optionally substituted alkyl.

In certain embodiments, the compound is of Formula IIe-2. In certainembodiments, the compound is of Formula IIe-3. In certain embodiments,the compound is of Formula IIe-4. In certain embodiments, the compoundis of Formula IIe-5. In certain embodiments, the compound is of FormulaIIe-6.

In certain embodiments, provided is a compound of Formula IIe-4 or apharmaceutically acceptable salt, prodrug, tautomer, stereoisomer ormixture of stereoisomers thereof;

wherein

q is 0, 1 or 2;

R¹ is H or C₁-C₆ alkyl;

Y² is —O— or —C(R⁶)²—;

each R⁶ is independently H, halo, or optionally substituted C₁-C₆ alkyl,or two R⁶ together with the carbon atom to which they are attached, forma C₁-C₆ alken-1-yl, optionally substituted cycloalkyl or optionallysubstituted heterocyclyl ring;

R³ and R⁴ are independently H, halo, or optionally substituted C₁-C₆alkyl, or R³ and R⁴ together with the carbon atoms to which they areattached, form an optionally substituted cycloalkyl or optionallysubstituted heterocyclyl ring, or R³ and R⁶ together with the carbonatoms to which they are attached, form an optionally substitutedcycloalkyl or optionally substituted heterocyclyl ring;

A is an optionally substituted cycloalkyl, optionally substitutedheterocyclyl, optionally substituted aryl or optionally substitutedheteroaryl ring;

L is absent, —O— or —C(R⁸)₂—;

each R⁸ is independently H, halo, or optionally substituted C₁-C₆ alkyl,or two R⁸ together with the carbon atom to which they are attached, forma optionally substituted cycloalkyl or optionally substitutedheterocyclyl ring;

R⁹ is optionally substituted cycloalkyl, optionally substitutedheterocyclyl, optionally substituted aryl or optionally substitutedheteroaryl; and

each R¹⁰ is independently cyano, halo, optionally substituted C₁-C₆alkyl or —S(O)₂—C₁-C₆ alkyl.

In certain embodiments, provided is a compound of Formula IIf:

or a pharmaceutically acceptable salt, prodrug, tautomer, stereoisomeror mixture of stereoisomers thereof;

wherein

q is 0, 1 or 2;

R¹ is H or C₁-C₆ alkyl optionally substituted with halo, hydroxy orcyano;

Y² is —O—, —S—, —S(O)—, —S(O)₂—, —S(O)(NH)—, —NR⁵— or —C(R⁶)₂—;

R⁵ is H or optionally substituted C₁-C₆ alkyl;

each R⁶ is independently H, halo, or optionally substituted C₁-C₆ alkyl,or two R⁶ together with the carbon atom to which they are attached, forma C₁-C₆ alken-1-yl, optionally substituted cycloalkyl or optionallysubstituted heterocyclyl ring;

R³ and R⁴ are independently H, halo, or optionally substituted C₁-C₆alkyl, or R³ and R⁴ together with the carbon atoms to which they areattached, form an optionally substituted cycloalkyl or optionallysubstituted heterocyclyl ring, or R³ and R⁶ together with the carbonatoms to which they are attached, form an optionally substitutedcycloalkyl or optionally substituted heterocyclyl ring;

A is an optionally substituted cycloalkyl, optionally substitutedheterocyclyl, optionally substituted aryl or optionally substitutedheteroaryl ring;

L is absent, —O—, —S—, —S(O)—, —S(O)₂—, —NR⁷— or —C(R⁸)₂—;

R⁷ is H or optionally substituted C₁-C₆ alkyl;

each R⁸ is independently H, halo, or optionally substituted C₁-C₆ alkyl,or two R⁸ together with the carbon atom to which they are attached, forma optionally substituted cycloalkyl or optionally substitutedheterocyclyl ring;

R⁹ is optionally substituted cycloalkyl, optionally substitutedheterocyclyl, optionally substituted aryl or optionally substitutedheteroaryl; and

each R¹⁰ is independently cyano, halo, optionally substituted C₁-C₆alkyl or —S(O)₂—C₁-C₆ alkyl.

In certain embodiments, the compound is of Formula IIf or apharmaceutically acceptable salt, prodrug, tautomer, stereoisomer ormixture of stereoisomers thereof;

wherein

q is 0, 1 or 2;

R¹ is H or C₁-C₆ alkyl optionally substituted with halo, hydroxy orcyano;

Y² is —O—, —S—, —S(O)—, —S(O)₂—, —S(O)(NH)—, —NR⁵— or —C(R⁶)₂—;

R¹ is H or optionally substituted C₁-C₆ alkyl;

each R⁶ is independently H, halo, or optionally substituted C₁-C₆ alkyl,or two R⁶ together with the carbon atom to which they are attached, forma C₁-C₆ alken-1-yl, optionally substituted cycloalkyl or optionallysubstituted heterocyclyl ring;

R³ and R⁴ are independently H, halo, or optionally substituted C₁-C₆alkyl, or R³ and R⁴ together with the carbon atoms to which they areattached, form an optionally substituted cycloalkyl or optionallysubstituted heterocyclyl ring, or R³ and R⁶ together with the carbonatoms to which they are attached, form an optionally substitutedcycloalkyl or optionally substituted heterocyclyl ring;

A is an optionally substituted cycloalkyl, optionally substitutedheterocyclyl, optionally substituted aryl or optionally substitutedheteroaryl ring;

L is absent, —O—, —S—, —S(O)—, —S(O)₂—, —NR⁷— or —C(R⁸)₂—;

R⁷ is H or optionally substituted C₁-C₆ alkyl;

each R⁸ is independently H, halo, or optionally substituted C₁-C₆ alkyl,or two R⁸ together with the carbon atom to which they are attached, forma optionally substituted cycloalkyl or optionally substitutedheterocyclyl ring;

R⁹ is optionally substituted cycloalkyl, optionally substitutedheterocyclyl, optionally substituted aryl or optionally substitutedheteroaryl; and

each R¹⁰ is independently cyano, halo or optionally substituted alkyl.

In certain embodiments, the compound is of Formula IIf wherein

R¹ is H or optionally substituted C₁-C₆ alkyl;

Y² is —O—, —S—, —S(O)—, —S(O)₂—, —S(O)(NH)—, —NR⁵— or —C(R⁶)₂—;

R⁵ is H or optionally substituted C₁-C₆ alkyl;

each R⁶ is independently H, halo, optionally substituted C₁-C₆ alkyl, ortwo R⁶ together with the carbon atom to which they are attached, form aC₁-C₆ alken-1-yl, optionally substituted cycloalkyl or optionallysubstituted heterocyclyl ring;

R³ and R⁴ are independently H, halo, optionally substituted C₁-C₆ alkyl,R³ and R⁴ together with the carbon atoms to which they are attached,form an optionally substituted cycloalkyl or optionally substitutedheterocyclyl ring, or R³ and R⁶ together with the carbon atoms to whichthey are attached, form an optionally substituted cycloalkyl oroptionally substituted heterocyclyl ring;

A is an optionally substituted cycloalkyl, optionally substitutedheterocyclyl ring or optionally substituted heteroaryl ring;

L is absent, —O—, —S—, —S(O)—, —S(O)₂—, —NR⁷— or —C(R⁸)₂—;

R⁷ is H or optionally substituted C₁-C₆ alkyl;

each R⁸ is independently H, halo, optionally substituted C₁-C₆ alkyl, ortwo R⁸ together with the carbon atom to which they are attached, form aoptionally substituted cycloalkyl or optionally substituted heterocyclylring; and

R⁹ is optionally substituted cycloalkyl, optionally substitutedheterocyclyl, optionally substituted aryl or optionally substitutedheteroaryl; provided that at least one of the following occurs:

(1) at least one of R³ and R⁴ are halo or optionally substituted C₁-C₆alkyl, R³ and R⁴ together with the carbon atoms to which they areattached, form an optionally substituted cycloalkyl or optionallysubstituted heterocyclyl ring, or R³ and R⁶ together with the carbonatoms to which they are attached, form a optionally substitutedcycloalkyl or optionally substituted heterocyclyl ring;

(2) L is absent or —C(R⁸)₂—, and two R⁸ together with the carbon atom towhich they are attached, form an optionally substituted cycloalkyl oroptionally substituted heterocyclyl ring; or

(3) Y² is —C(R⁶)₂—; and two R⁶ together with the carbon atom to whichthey are attached, form a C₁-C₆ alken-1-yl, optionally substitutedcycloalkyl or optionally substituted heterocyclyl ring;

or a pharmaceutically acceptable salt, prodrug, tautomer, stereoisomeror mixture of stereoisomers thereof.

In certain embodiments, provided is a compound of Formula IIf or apharmaceutically acceptable salt, prodrug, tautomer, stereoisomer ormixture of stereoisomers thereof;

wherein

q is 0, 1 or 2;

R¹ is H or C₁-C₆ alkyl;

Y² is —O— or —C(R⁶)₂—;

each R⁶ is independently H, halo, or optionally substituted C₁-C₆ alkyl,or two R⁶ together with the carbon atom to which they are attached, forma C₁-C₆ alken-1-yl, optionally substituted cycloalkyl or optionallysubstituted heterocyclyl ring;

R³ and R⁴ are independently H, halo, or optionally substituted C₁-C₆alkyl, or R³ and R⁴ together with the carbon atoms to which they areattached, form an optionally substituted cycloalkyl or optionallysubstituted heterocyclyl ring, or R³ and R⁶ together with the carbonatoms to which they are attached, form an optionally substitutedcycloalkyl or optionally substituted heterocyclyl ring;

A is an optionally substituted cycloalkyl, optionally substitutedheterocyclyl, optionally substituted aryl or optionally substitutedheteroaryl ring;

L is absent, —O— or —C(R⁸)₂—;

each R⁸ is independently H, halo, or optionally substituted C₁-C₆ alkyl,or two R⁸ together with the carbon atom to which they are attached, forma optionally substituted cycloalkyl or optionally substitutedheterocyclyl ring;

R⁹ is optionally substituted cycloalkyl, optionally substitutedheterocyclyl, optionally substituted aryl or optionally substitutedheteroaryl; and

each R¹⁰ is independently cyano, halo, optionally substituted C₁-C₆alkyl or —S(O)₂—C₁-C₆ alkyl.

In certain embodiments, the compound is of Formula IIf-1:

wherein

or a pharmaceutically acceptable salt, prodrug, tautomer, stereoisomeror mixture of stereoisomers thereof;

q is 0, 1 or 2;

R¹ is H or C₁-C₆ alkyl optionally substituted with halo, hydroxy orcyano;

R⁴ is H, halo, or optionally substituted C₁-C₆ alkyl;

A is an optionally substituted cycloalkyl, optionally substitutedheterocyclyl, optionally substituted aryl or optionally substitutedheteroaryl ring;

L is absent, —O—, —S—, —S(O)—, —S(O)₂—, —NR⁷— or —C(R⁸)₂—;

R⁷ is H or optionally substituted C₁-C₆ alkyl;

each R⁸ is independently H, halo, or optionally substituted C₁-C₆ alkyl,or two R⁸ together with the carbon atom to which they are attached, forma optionally substituted cycloalkyl or heterocyclyl ring;

R⁹ is optionally substituted cycloalkyl, optionally substitutedheterocyclyl, optionally substituted aryl or optionally substitutedheteroaryl; and

each R¹⁰ is independently cyano, halo or optionally substituted alkyl.

In certain embodiments, the compound is of Formula IIf-2. In certainembodiments, the compound is of Formula IIf-3. In certain embodiments,the compound is of Formula IIf-4. In certain embodiments, the compoundis of Formula IIf-5. In certain embodiments, the compound is of FormulaIIf-6.

In certain embodiments, provided is a compound of Formula IIf-4 or apharmaceutically acceptable salt, prodrug, tautomer, stereoisomer ormixture of stereoisomers thereof;

wherein

q is 0, 1 or 2;

R¹ is H or C₁-C₆ alkyl;

Y² is —O— or —C(R⁶)₂—;

each R⁶ is independently H, halo, or optionally substituted C₁-C₆ alkyl,or two R⁶ together with the carbon atom to which they are attached, forma C₁-C₆ alken-1-yl, optionally substituted cycloalkyl or optionallysubstituted heterocyclyl ring;

R³ and R⁴ are independently H, halo, or optionally substituted C₁-C₆alkyl, or R³ and R⁴ together with the carbon atoms to which they areattached, form an optionally substituted cycloalkyl or optionallysubstituted heterocyclyl ring, or R³ and R⁶ together with the carbonatoms to which they are attached, form an optionally substitutedcycloalkyl or optionally substituted heterocyclyl ring;

A is an optionally substituted cycloalkyl, optionally substitutedheterocyclyl, optionally substituted aryl or optionally substitutedheteroaryl ring;

L is absent, —O— or —C(R⁸)₂—;

each R⁸ is independently H, halo, or optionally substituted C₁-C₆ alkyl,or two R⁸ together with the carbon atom to which they are attached, forma optionally substituted cycloalkyl or optionally substitutedheterocyclyl ring;

R⁹ is optionally substituted cycloalkyl, optionally substitutedheterocyclyl, optionally substituted aryl or optionally substitutedheteroaryl; and

each R¹⁰ is independently cyano, halo, optionally substituted C₁-C₆alkyl or —S(O)₂—C₁-C₆ alkyl.

In certain embodiments of compounds of Formula I (or subformulathereof), R³ is H. In certain embodiments of compounds of Formula I (orsubformula thereof), R⁴ is optionally substituted C₁-C₆ alkyl. Incertain embodiments of compounds of Formula I (or subformula thereof),R³ is H and R⁴ is optionally substituted C₁-C₆ alkyl. In certainembodiments of compounds of Formula I (or subformula thereof), R³ is Hand R⁴ is methyl.

In certain embodiments of compounds of Formula I (or subformulathereof), R³ is H and R⁴ is H.

In certain embodiments of compounds of Formula II (or subformulathereof), R³ is H. In certain embodiments of compounds of Formula II (orsubformula thereof), R⁴ is optionally substituted C₁-C₆ alkyl. Incertain embodiments of compounds of Formula II (or subformula thereof),R³ is H and R⁴ is optionally substituted C₁-C₆ alkyl. In certainembodiments of compounds of Formula II (or subformula thereof), R³ is Hand R⁴ is C₁-C₆ alkyl. In certain embodiments of compounds of Formula II(or subformula thereof), R³ is H and R⁴ is methyl.

In certain embodiments of compounds of Formula IIa, IIb, IIc, IId, IIeand IIf (or subformula thereof), R³ is H and R⁴ is H. In certainembodiments of compounds of Formula IIe-4 and IIe-5, R³ is H and R⁴ isH.

In certain embodiments of compounds of Formula I (or subformulathereof), the A ring is an optionally substituted heteroaryl ring. Incertain embodiments of compounds of Formula I (or subformula thereof),the A ring is an unsubstituted heteroaryl ring. In certain embodimentsof compounds of Formula I (or subformula thereof), the A ring is apyrazolyl, isoxazolyl, oxadiazolyl or triazolyl. In certain embodimentsof compounds of Formula I (or subformula thereof), the A ring is aoxadiazolyl. In certain embodiments of compounds of Formula I (orsubformula thereof), the A ring is a triazolyl.

In certain embodiments of compounds of Formula II (or subformulathereof), the A ring is an optionally substituted heteroaryl ring. Incertain embodiments of compounds of Formula II (or subformula thereof),the A ring is an unsubstituted heteroaryl ring. In certain embodimentsof compounds of Formula II (or subformula thereof), the A ring is anoptionally substituted 5-membered heteroaryl ring. In certainembodiments of compounds of Formula II (or subformula thereof), the Aring is an unsubstituted 5-membered heteroaryl ring. In certainembodiments of compounds of Formula II (or subformula thereof), the Aring is an optionally substituted 6-membered heteroaryl ring. In certainembodiments of compounds of Formula II (or subformula thereof), the Aring is a heteroaryl ring substituted with at least one halo. In certainembodiments of compounds of Formula II (or subformula thereof), the Aring is a 5-membered heteroaryl ring substituted with at least one halo.In certain embodiments of compounds of Formula II (or subformulathereof), the A ring is a pyrazolyl, isoxazolyl, oxadiazolyl ortriazolyl. In certain embodiments of compounds of Formula II (orsubformula thereof), the A ring is oxadiazolyl. In certain embodimentsof compounds of Formula II (or subformula thereof), the A ring is atriazolyl.

In certain embodiments of compounds of Formula II (or subformulathereof), the A ring is of the formula:

wherein

X¹⁰, X¹¹ and X¹² are each S, O, N, CR¹³ or NR¹³, and X¹³ is C or N; and

each R¹³ is independently H, halo, cyano or optionally substituted C₁-C₆alkyl.

In certain embodiments, at least one of X¹⁰, X¹¹ and X¹² is CR¹³ or NR¹³and at least one R¹³ is halo, cyano or optionally substituted C₁-C₆alkyl. In certain embodiments, at least one of X¹⁰, X¹¹ and X¹² is CR¹³or NR¹³ and at least one R¹³ is halo. In certain embodiments, each R¹³is independently H, fluoro, chloro, cyano or methyl.

In certain embodiments of compounds of Formula II (or subformulathereof), the A ring is one of the following:

wherein each ring may optionally substituted with one or more halo,cyano or C₁-C₆ alkyl.

In certain embodiments of compounds of Formula II (or subformulathereof), the A ring is one of the following:

In certain embodiments of compounds of Formula I (or subformulathereof), L is absent, —O— or —C(R⁸)₂—; and each R⁸ is independently Hor C₁-C₆ alkyl, or two R⁸ together with the carbon atom to which theyare attached, form a optionally substituted cycloalkyl. In certainembodiments of compounds of Formula I (or subformula thereof), L is—C(R⁸)₂— and each R⁸ is taken together with the carbon atom to whichthey are attached to form cyclopropyl.

In certain embodiments of compounds of Formula II (or subformulathereof), L is absent, —O— or —C(R⁸)₂—; and each R⁸ is independently H,halo, or optionally substituted C₁-C₆ alkyl, or two R⁸ together with thecarbon atom to which they are attached, form a optionally substitutedcycloalkyl or optionally substituted heterocyclyl ring. In certainembodiments of compounds of Formula II (or subformula thereof), L isabsent, —O— or —C(R⁸)₂—; and each R⁸ is independently H or two R⁸together with the carbon atom to which they are attached, form aoptionally substituted cycloalkyl.

In certain embodiments of compounds of Formula II (or subformulathereof), L is absent. In certain embodiments of compounds of Formula II(or subformula thereof), L is —O—. In certain embodiments of compoundsof Formula II (or subformula thereof), L is —C(R⁸)₂— and each R⁸ isindependently H, halo, or optionally substituted C₁-C₆ alkyl, or two R⁸together with the carbon atom to which they are attached, form aoptionally substituted cycloalkyl or optionally substituted heterocyclylring. In certain embodiments of compounds of Formula II (or subformulathereof), L is —C(R⁸)₂— and each R⁸ is independently H, or two R⁸together with the carbon atom to which they are attached, form aoptionally substituted cycloalkyl. In certain embodiments of compoundsof Formula II (or subformula thereof), L is —C(R⁸)₂— and each R⁸ istaken together with the carbon atom to which they are attached to formcyclopropyl.

In certain embodiments of compounds of Formula I (or subformulathereof), R⁹ is optionally substituted aryl. In certain embodiments ofcompounds of Formula I (or subformula thereof), R⁹ is phenyl optionallysubstituted with one or more halo, cyano or C₁-C₆ alkyl optionallysubstituted with halo. In certain embodiments of compounds of Formula I(or subformula thereof), R⁹ is phenyl.

In certain embodiments of compounds of Formula II (or subformulathereof), R⁹ is optionally substituted cycloalkyl, optionallysubstituted aryl or optionally substituted heteroaryl. In certainembodiments of compounds of Formula II (or subformula thereof), R⁹ isphenyl, dihydroindenyl, pyridyl, 2-fluorophenyl, 3-fluorophenyl,4-fluorophenyl, 2-cyanophenyl, 3-cyanophenyl, 4-cyanophenyl,2,4-difluorophenyl, 3-cyano-4-fluorophenyl, or 5-fluoropyridin-3-yl.

In certain embodiments of compounds of Formula II (or subformulathereof), q is 0. In certain embodiments of compounds of Formula II (orsubformula thereof), q is 1 or 2; and each R¹⁰ is independently cyano,halo, optionally substituted C₁-C₆ alkyl, or —S(O)₂—C₁-C₆ alkyl. Incertain embodiments of compounds of Formula II (or subformula thereof),q is 1 or 2; and each R¹⁰ is independently cyano, halo, methyl, or—S(O)₂-methyl.

In certain embodiments, the compound is of Formula III:

or a pharmaceutically acceptable salt, prodrug, tautomer, stereoisomeror mixture of stereoisomers thereof;

wherein

q is 0, 1 or 2;

R¹ is H or C₁-C₆ alkyl optionally substituted with halo, hydroxy orcyano;

X¹ and X² are each N or CH;

X³, X⁴ and X⁵ are each S, O, N, NH, or CH

Y² is —O—, —S—, —S(O)—, —S(O)₂—, —S(O)(NH)—, —NR⁵— or —C(R⁶)₂—;

R⁵ is H or optionally substituted C₁-C₆ alkyl;

each R⁶ is independently H, halo, or optionally substituted C₁-C₆ alkyl,or two R⁶ together with the carbon atom to which they are attached, forma C₁-C₆ alken-1-yl, optionally substituted cycloalkyl or optionallysubstituted heterocyclyl ring;

R³ and R⁴ are independently H, halo, or optionally substituted C₁-C₆alkyl, or R³ and R⁴ together with the carbon atoms to which they areattached, form an optionally substituted cycloalkyl or optionallysubstituted heterocyclyl ring, or R³ and R⁶ together with the carbonatoms to which they are attached, form an optionally substitutedcycloalkyl or optionally substituted heterocyclyl ring;

A is an optionally substituted cycloalkyl, optionally substitutedheterocyclyl, optionally substituted aryl or optionally substitutedheteroaryl ring;

L is absent, —O—, —S—, —S(O)—, —S(O)₂—, —NR⁷— or —C(R⁸)₂—;

R⁷ is H or optionally substituted C₁-C₆ alkyl;

each R⁸ is independently H, halo, or optionally substituted C₁-C₆ alkyl,or two R⁸ together with the carbon atom to which they are attached, forma optionally substituted cycloalkyl or optionally substitutedheterocyclyl ring;

R⁹ is optionally substituted cycloalkyl, optionally substitutedheterocyclyl, optionally substituted aryl or optionally substitutedheteroaryl; and

each R¹⁰ is independently cyano, halo or optionally substituted alkyl.

In certain embodiments, at least one of the following occurs:

(1) at least one of R³ and R⁴ are halo or optionally substituted C₁-C₆alkyl, or R³ and R⁴ together with the carbon atoms to which they areattached, form an optionally substituted cycloalkyl or optionallysubstituted heterocyclyl ring, or R³ and R⁶ together with the carbonatoms to which they are attached, form a optionally substitutedcycloalkyl or optionally substituted heterocyclyl ring;

(2) L is absent or —C(R⁸)₂—, and each R⁸ is optionally substituted C₁-C₆alkyl or halo or two R⁸ together with the carbon atom to which they areattached, form an optionally substituted cycloalkyl or optionallysubstituted heterocyclyl ring; or

(3) Y² is —C(R⁶)₂—; and one R⁶ is hydrogen, halo, or optionallysubstituted C₁-C₆ alkyl, and the other R⁶ is halo or optionallysubstituted C₁-C₆ alkyl; or two R⁶ together with the carbon atom towhich they are attached, form a C₁-C₆ alken-1-yl, optionally substitutedcycloalkyl or optionally substituted heterocyclyl ring.

In certain embodiments, the compound is of Formula III wherein

X¹ and X² are each N or CH;

X³, X⁴ and X⁵ are each S, O, N, NH, or CH

Y² is —O—, —S—, —S(O)—, —S(O)₂—, —S(O)(NH)—, —NR⁵— or —C(R⁶)₂—;

R⁵ is H or optionally substituted C₁-C₆ alkyl;

each R⁶ is independently H, halo, optionally substituted C₁-C₆ alkyl, ortwo R⁶ together with the carbon atom to which they are attached, form aC₁-C₆ alken-1-yl, optionally substituted cycloalkyl or optionallysubstituted heterocyclyl ring;

R³ and R⁴ are independently H, halo, optionally substituted C₁-C₆ alkyl,R³ and R⁴ together with the carbon atoms to which they are attached,form an optionally substituted cycloalkyl or optionally substitutedheterocyclyl ring, or R³ and R⁶ together with the carbon atoms to whichthey are attached, form an optionally substituted cycloalkyl oroptionally substituted heterocyclyl ring;

A is an optionally substituted cycloalkyl, optionally substitutedheterocyclyl ring or optionally substituted heteroaryl ring;

L is absent, —O—, —S—, —S(O)—, —S(O)₂—, —NR⁷— or —C(R⁸)₂—;

R⁷ is H or optionally substituted C₁-C₆ alkyl;

each R⁸ is independently H, halo, optionally substituted C₁-C₆ alkyl, ortwo R⁸ together with the carbon atom to which they are attached, form aoptionally substituted cycloalkyl or optionally substituted heterocyclylring; and

R⁹ is optionally substituted cycloalkyl, optionally substitutedheterocyclyl, optionally substituted aryl or optionally substitutedheteroaryl;

or a pharmaceutically acceptable salt, prodrug, tautomer, stereoisomeror mixture of stereoisomers thereof.

In certain embodiments, the compound is of Formula IIIa, IIIb, or IIIc:

or a pharmaceutically acceptable salt, prodrug, tautomer, stereoisomeror mixture of stereoisomers thereof;

wherein

q is 0, 1 or 2;

R¹ is H or C₁-C₆ alkyl optionally substituted with halo, hydroxy orcyano;

X³, X⁴ and X⁵ are each S, O, N, NH, or CH

Y² is —O—, —S—, —S(O)—, —S(O)₂—, —S(O)(NH)—, —NR⁵— or —C(R⁶)₂—;

R¹ is H or C₁-C₆ alkyl;

R⁵ is H or optionally substituted C₁-C₆ alkyl;

each R⁶ is independently H, halo, or optionally substituted C₁-C₆ alkyl,or two R⁶ together with the carbon atom to which they are attached, forma C₁-C₆ alken-1-yl, optionally substituted cycloalkyl or optionallysubstituted heterocyclyl ring;

R³ and R⁴ are independently H, halo, or optionally substituted C₁-C₆alkyl, or R³ and R⁴ together with the carbon atoms to which they areattached, form an optionally substituted cycloalkyl or optionallysubstituted heterocyclyl ring, or R³ and R⁶ together with the carbonatoms to which they are attached, form an optionally substitutedcycloalkyl or optionally substituted heterocyclyl ring;

A is an optionally substituted cycloalkyl, optionally substitutedheterocyclyl, optionally substituted aryl or optionally substitutedheteroaryl ring;

L is absent, —O—, —S—, —S(O)—, —S(O)₂—, —NR⁷— or —C(R⁸)₂—;

R⁷ is H or optionally substituted C₁-C₆ alkyl;

each R⁸ is independently H, halo, or optionally substituted C₁-C₆ alkyl,or two R⁸ together with the carbon atom to which they are attached, forma optionally substituted cycloalkyl or optionally substitutedheterocyclyl ring;

R⁹ is optionally substituted cycloalkyl, optionally substitutedheterocyclyl, optionally substituted aryl or optionally substitutedheteroaryl; and

each R¹⁰ is independently cyano, halo or optionally substituted alkyl.

In certain embodiments, the compound is of Formula IIIa-1, IIIb-1, orIIIc-1:

or a pharmaceutically acceptable salt, prodrug, tautomer, stereoisomeror mixture of stereoisomers thereof;

wherein

q is 0, 1 or 2;

R¹ is H or C₁-C₆ alkyl optionally substituted with halo, hydroxy orcyano;

X³, X⁴ and X⁵ are each S, O, N, NH, or CH;

R¹ is H or C₁-C₆ alkyl;

R⁴ is H, halo, or optionally substituted C₁-C₆ alkyl;

A is an optionally substituted cycloalkyl, optionally substitutedheterocyclyl, optionally substituted aryl or optionally substitutedheteroaryl ring;

L is absent, —O—, —S—, —S(O)—, —S(O)₂—, —NR⁷— or —C(R⁸)₂—;

R⁷ is H or optionally substituted C₁-C₆ alkyl;

each R⁸ is independently H, halo, or optionally substituted C₁-C₆ alkyl,or two R⁸ together with the carbon atom to which they are attached, forma optionally substituted cycloalkyl or optionally substitutedheterocyclyl ring;

R⁹ is optionally substituted cycloalkyl, optionally substitutedheterocyclyl, optionally substituted aryl or optionally substitutedheteroaryl; and

each R¹⁰ is independently cyano, halo or optionally substituted alkyl.

In certain embodiments, the compound is of Formula IIIa, IIIb, or IIIc:

wherein

X³, X⁴ and X⁵ are each S, O, N, NH, or CH

Y² is —O—, —S—, —S(O)—, —S(O)₂—, —S(O)(NH)—, —NR⁵— or —C(R⁶)₂—;

R⁵ is H or optionally substituted C₁-C₆ alkyl;

each R⁶ is independently H, halo, optionally substituted C₁-C₆ alkyl, ortwo R⁶ together with the carbon atom to which they are attached, form aC₁-C₆ alken-1-yl, optionally substituted cycloalkyl or optionallysubstituted heterocyclyl ring;

R³ and R⁴ are independently H, halo, optionally substituted C₁-C₆ alkyl,R³ and R⁴ together with the carbon atoms to which they are attached,form an optionally substituted cycloalkyl or optionally substitutedheterocyclyl ring, or R³ and R⁶ together with the carbon atoms to whichthey are attached, form an optionally substituted cycloalkyl oroptionally substituted heterocyclyl ring;

A is an optionally substituted cycloalkyl, optionally substitutedheterocyclyl ring or optionally substituted heteroaryl ring;

L is absent, —O—, —S—, —S(O)—, —S(O)₂—, —NR⁷— or —C(R⁸)₂—;

R⁷ is H or optionally substituted C₁-C₆ alkyl;

each R⁸ is independently H, halo, optionally substituted C₁-C₆ alkyl, ortwo R⁸ together with the carbon atom to which they are attached, form aoptionally substituted cycloalkyl or optionally substituted heterocyclylring; and

R⁹ is optionally substituted cycloalkyl, optionally substitutedheterocyclyl, optionally substituted aryl or optionally substitutedheteroaryl;

or a pharmaceutically acceptable salt, prodrug, tautomer, stereoisomeror mixture of stereoisomers thereof.

In certain embodiments, the compound is of Formula IIIa-1, IIIa-2,IIIa-3, IIIa-4, IIIa-5, IIIa-6, IIIa-7, IIIa-8 or IIIa-9:

wherein the variables of Formula IIIa-1 to IIIa-9 are definedthroughout.

In certain embodiments, the compound is of Formula IVa, IVb, IVc, IVd,IVe, IVf or IVg:

or a pharmaceutically acceptable salt, prodrug, tautomer, stereoisomeror mixture of stereoisomers thereof;

wherein

q is 0, 1 or 2;

R⁴ is H, halo, or optionally substituted C₁-C₆ alkyl;

A is an optionally substituted cycloalkyl, optionally substitutedheterocyclyl, optionally substituted aryl or optionally substitutedheteroaryl ring;

L is absent, —O—, —S—, —S(O)—, —S(O)₂—, —NR⁷— or —C(R⁸)₂—;

R⁷ is H or optionally substituted C₁-C₆ alkyl;

each R⁸ is independently H, halo, or optionally substituted C₁-C₆ alkyl,or two R⁸ together with the carbon atom to which they are attached, forma optionally substituted cycloalkyl or optionally substitutedheterocyclyl ring;

R⁹ is optionally substituted cycloalkyl, optionally substitutedheterocyclyl, optionally substituted aryl or optionally substitutedheteroaryl; and

each R¹⁰ is independently cyano, halo, optionally substituted C₁-C₆alkyl, or —S(O)₂—C₁-C₆ alkyl.

In certain embodiments, provided is a compound of Formula V:

or a pharmaceutically acceptable salt, prodrug, tautomer, stereoisomeror mixture of stereoisomers thereof, wherein

q is 0, 1, or 2;

X⁶ and X⁹ are independently N or CR¹⁴;

R¹ is H or optionally substituted C₁-C₆ alkyl;

Y² is —O— or —C(R⁶)₂—;

each R⁶ is independently H, halo, optionally substituted C₁-C₆ alkyl;

R³ is H, halo, optionally substituted C₁-C₆ alkyl, or R³ and R⁶ togetherwith the carbon atoms to which they are attached, form an optionallysubstituted cycloalkyl or optionally substituted heterocyclyl ring;

L is —C(R⁸)₂—;

each R⁸ is independently H, halo, optionally substituted C₁-C₆ alkyl, ortwo R⁸ together with the carbon atom to which they are attached form anoptionally substituted cycloalkyl or optionally substituted heterocyclylring;

R⁹ is optionally substituted aryl or optionally substituted heteroaryl;

each R¹⁰ is independently cyano, halo, optionally substituted C₁-C₆alkyl, optionally substituted heteroaryl, optionally substituted aryl,optionally substituted heterocyclyl, optionally substituted cycloalkyl,optionally substituted C₁-C₆ alkoxy, or —S(O)₂—C₁-C₆ alkyl; and

each R¹⁴ is independently hydrogen, cyano, halo, C₁-C₃ alkyl optionallysubstituted with halo, or C₁-C₃ alkoxy optionally substituted with halo;

provided that when both of X⁶ and X⁹ are CR¹⁴, one or more of (i), (ii),(iii), (iv) and (v) is true: (i) R³ and R⁶ together with the carbonatoms to which they are attached form an optionally substitutedcycloalkyl or optionally substituted heterocyclyl ring, (ii) L is—C(R⁸)₂— and each R⁸ is taken together with the carbon atom to whichthey are attached to form cyclopropyl, (iii) R⁹ is substituted with atleast one cyano, (iv) X⁹ is other than C—H, C—F, C—Cl or C—CH₃ and/or(v) X⁶ is other than C—H, C—F or C—CH₃.

In certain embodiments of compounds of Formula V (or subformulathereof), X⁹ is N. In certain embodiments X⁹ is N and X⁶ is CR¹⁴. Incertain embodiments X⁹ and X⁶ are N.

In certain embodiments of compounds of Formula V (or subformulathereof), Y² is O. In certain embodiments R³ is H. In certainembodiments R³ is methyl. In certain embodiments R³ and R⁶ together withthe carbon atoms to which they are attached form an optionallysubstituted cycloalkyl. In certain embodiments R³ and R⁶ together withthe carbon atoms to which they are attached form an optionallysubstituted cyclopropyl ring.

In certain embodiments of compounds of Formula V (or subformulathereof), X⁶ and X⁹ are CR¹⁴ and R³ and R⁶ together with the carbonatoms to which they are attached form an optionally substitutedcycloalkyl. In certain embodiments R³ and R⁶ together with the carbonatoms to which they are attached form an optionally substitutedcyclopropyl ring. In certain embodiments X⁹ is CH. In certainembodiments X⁹ is CF.

In certain embodiments of compounds of Formula V (or subformulathereof), X⁶ and X⁹ are CR¹⁴ and L is —C(R⁸)₂— and each R⁸ is takentogether with the carbon atom to which they are attached to formcyclopropyl.

In certain embodiments of compounds of Formula V (or subformulathereof), X⁶ and X⁹ are CR¹⁴, L is —C(R⁸)₂— and each R⁸ is takentogether with the carbon atom to which they are attached to formcyclopropyl and R³ and R⁶ together with the carbon atoms to which theyare attached form an optionally substituted cyclopropyl ring.

In certain embodiments of compounds of Formula V (or subformulathereof), each R¹⁰ is independently cyano, halo, or —S(O)₂—C₁-C₆ alkyl.In certain embodiments, q is 1 or 2 and each R¹⁰ is independently cyano,halo, or —S(O)₂—C₁-C₆ alkyl. In certain embodiments, q is two and bothR¹⁰ are halo. In certain embodiments, q is two and both R¹⁰ are fluoro.In certain embodiments, q is two and at least one R¹⁰ is fluoro.

In certain embodiments of compounds of Formula V (or subformulathereof), R¹ is H or methyl. In certain embodiments of compounds ofFormula V (or subformula thereof), R¹ is H.

In certain embodiments of compounds of Formula V (or subformulathereof), R¹ is methyl.

In certain embodiments of compounds of Formula V (or subformulathereof), L is CH₂ or two R⁸ together with the carbon atom to which theyare attached form a cycloalkyl ring. In certain embodiments L is CH₂. Incertain embodiments R⁹ is optionally substituted phenyl. In certainembodiments R⁹ is phenyl. In certain embodiments R⁹ is phenylsubstituted by one to two substituents independently selected from thegroup consisting of cyano and halo. In certain embodiments R⁹ is phenylsubstituted by cyano.

In certain embodiments of compounds of Formula V (or subformulathereof), R¹⁴ is hydrogen, halo or methyl optionally substituted with1-3 fluoro. In certain embodiments, R¹⁴ is hydrogen or halo. In certainembodiments, R¹⁴ is hydrogen. In certain embodiments, R¹⁴ is halo. Incertain embodiments, R¹⁴ is fluoro.

In certain embodiments, provided is a compound of Formula Va:

or a pharmaceutically acceptable salt, prodrug, tautomer, stereoisomeror mixture of stereoisomers thereof, wherein

q is 0, 1, or 2;

X⁶ is N or CR¹⁴;

R¹ is H or optionally substituted C₁-C₆ alkyl;

Y² is —O— or —C(R⁶)₂—;

each R⁶ is independently H, halo, optionally substituted C₁-C₆ alkyl;

R³ is H, halo, optionally substituted C₁-C₆ alkyl, or R³ and R⁶ togetherwith the carbon atoms to which they are attached form an optionallysubstituted cycloalkyl or optionally substituted heterocyclyl ring;

L is —C(R⁸)₂—;

each R⁸ is independently H, halo, optionally substituted C₁-C₆ alkyl, ortwo R⁸ together with the carbon atom to which they are attached form aoptionally substituted cycloalkyl or optionally substituted heterocyclylring;

R⁹ is optionally substituted aryl or optionally substituted heteroaryl;

each R¹⁰ is independently cyano, halo, optionally substituted C₁-C₆alkyl, optionally substituted heteroaryl, optionally substituted aryl,optionally substituted heterocyclyl, optionally substituted cycloalkyl,optionally substituted C₁-C₆ alkoxy, or —S(O)₂—C₁-C₆ alkyl; and

R¹⁴ is hydrogen, cyano, halo, C₁-C₃ alkyl optionally substituted withhalo or oxo, or C₁-C₃ alkoxy optionally substituted with halo or oxo.

In certain embodiments of compounds of Formula Va, X⁶ is CR¹⁴. Incertain embodiments X⁶ is N.

In certain embodiments of compounds of Formula Va, each R¹⁰ isindependently cyano, halo, or —S(O)₂—C₁-C₆ alkyl. In certainembodiments, q is at least one and at least one R¹⁰ is halo. In certainembodiments, q is at least one and at least one R¹⁰ is fluoro. Incertain embodiments, q is at least one and at least one R¹⁰ is cyano.

In certain embodiments of compounds of Formula Va, q is 0.

In certain embodiments of compounds of Formula Va, Y² is O. In certainembodiments R³ is H. In certain embodiments R³ is methyl. In certainembodiments R³ and R⁶ together with the carbon atoms to which they areattached form an optionally substituted cycloalkyl. In certainembodiments R³ and R⁶ together with the carbon atoms to which they areattached form an optionally substituted cyclopropyl ring.

In certain embodiments of compounds of Formula Va, R¹ is H or methyl.

In certain embodiments of compounds of Formula Va, R¹ is methyl.

In certain embodiments of compounds of Formula Va, L is CH₂ or two Rtogether with the carbon atom to which they are attached form acycloalkyl ring. In certain embodiments L is CH₂.

In certain embodiments of compounds of Formula Va, R⁹ is optionallysubstituted phenyl. In certain embodiments R⁹ is phenyl. In certainembodiments R⁹ is phenyl substituted by one to two substituentsindependently selected from the group consisting of cyano and halo. Incertain embodiments R⁹ is phenyl substituted by cyano.

In certain embodiments of compounds of Formula Va (or subformulathereof), R¹⁴ is hydrogen, cyano, halo or methyl optionally substitutedwith 1-3 fluoro or oxo. In certain embodiments, R¹⁴ is hydrogen or halo.In certain embodiments, R¹⁴ is hydrogen. In certain embodiments, R¹⁴ iscyano.

In certain embodiments the compounds of Formula V and Va do not readilycross the blood brain barrier. In certain embodiments the compounds ofFormula V and Va have a MDCKII-MDR1 efflux ratio of greater than 2.5. Incertain embodiments the compounds of Formula II, Va and V wherein atleast one of X⁶ and X⁹ are N, have a hepatic clearance of less than 5,4, 3, 2, or 1 mL/min/kg when tested according to the human hepaticstability assay described below.

In certain embodiments, the compound is of Formula VI:

or a pharmaceutically acceptable salt, prodrug, tautomer, stereoisomeror mixture of stereoisomers thereof, wherein

q is 0, 1, or 2;

X⁶ is N or CR¹⁴;

R¹ is H or optionally substituted C₁-C₆ alkyl;

Y² is —O— or —C(R⁶)₂—;

each R⁶ is independently H, halo, optionally substituted C₁-C₆ alkyl;

R³ is H, halo, optionally substituted C₁-C₆ alkyl, or R³ and R⁶ togetherwith the carbon atoms to which they are attached, form an optionallysubstituted cycloalkyl or optionally substituted heterocyclyl ring;

L is —C(R⁸)₂—;

each R⁸ is independently H, halo, optionally substituted C₁-C₆ alkyl, ortwo R⁸ together with the carbon atom to which they are attached form aoptionally substituted cycloalkyl or optionally substituted heterocyclylring;

R⁹ is optionally substituted aryl;

each R¹⁰ is independently halo, optionally substituted C₁-C₆ alkyl,optionally substituted heteroaryl, optionally substituted aryl,optionally substituted heterocyclyl, optionally substituted cycloalkyl,or optionally substituted C₁-C₆ alkoxy; and

R¹⁴ is hydrogen, cyano, halo, C₁-C₃ alkyl optionally substituted withhalo or oxo, or C₁-C₃ alkoxy optionally substituted with halo or oxo.

In certain embodiments of compounds of Formula VI, X⁶ is CR¹⁴. Incertain embodiments X⁶ is N.

In certain embodiments of compounds of Formula VI, each R¹⁰ isindependently halo. In certain embodiments, q is one and R¹⁰ is fluoro.

In certain embodiments of compounds of Formula VI, Y² is O. In certainembodiments R³ is H. In certain embodiments R³ is methyl. In certainembodiments R³ and R⁶ together with the carbon atoms to which they areattached form an optionally substituted cycloalkyl. In certainembodiments R³ and R⁶ together with the carbon atoms to which they areattached form an optionally substituted cyclopropyl ring.

In certain embodiments of compounds of Formula VI, R¹ is H or methyl. Incertain embodiments of compounds of Formula VI, R¹ is methyl.

In certain embodiments of compounds of Formula VI, L is CH₂ or two Rtogether with the carbon atom to which they are attached form acycloalkyl ring. In certain embodiments L is CH₂.

In certain embodiments of compounds of Formula VI, R⁹ is phenyl. Incertain embodiments R⁹ is optionally substituted phenyl. In certainembodiments R⁹ is phenyl substituted by one to two halo.

In certain embodiments of compounds of Formula VI, R¹⁴ is hydrogen, haloor methyl optionally substituted with 1-3 fluoro or oxo. In certainembodiments, R¹⁴ is hydrogen or halo. In certain embodiments, R¹⁴ ishydrogen.

In certain embodiments the compounds of Formula VI readily cross theblood brain barrier. In certain embodiments the compounds of Formula VIhave a MDCKII-MDR1 efflux ratio of 2.5 or less. In certain embodimentsthe compounds of Formula VI have a hepatic clearance of less than 10, 9,8, 7, 6, 5, 4, 3, 2, or 1 μL/min/kg when tested according to the humanhepatic stability assay described below.

In any of the embodiments described throughout, q is 0, 1 or 2; and eachR¹⁰ is independently cyano, halo or optionally substituted alkyl. In anyof the embodiments described throughout, q is 0, 1 or 2; and each R¹⁰ isindependently cyano, halo, or alkyl optionally substituted with 1-3 haloor oxo.

In any of the embodiments described throughout, q is 0, 1 or 2; and eachR¹⁰ is independently cyano, halo, optionally substituted C₁-C₆ alkyl, or—S(O)₂—C₁-C₆ alkyl. In any of the embodiments described throughout, q is1 or 2; and each R¹⁰ is independently cyano, halo, optionallysubstituted C₁-C₆ alkyl, or —S(O)₂—C₁-C₆ alkyl. In any of theembodiments described throughout, q is 0, 1 or 2; and each R¹ isindependently cyano, fluoro, chloro, bromo, methyl, trifluoromethyl, or—S(O)₂-methyl. In any of the embodiments described throughout, q is 1 or2; and each R¹⁰ is independently cyano, fluoro, chloro, bromo, methyl,trifluoromethyl, or —S(O)₂-methyl.

In any of the embodiments described throughout, the A ring is anoptionally substituted heteroaryl ring. In any of the embodimentsdescribed throughout, the A ring is an unsubstituted heteroaryl ring. Inany of the embodiments described throughout, the A ring is an optionallysubstituted 5-membered heteroaryl ring. In any of the embodimentsdescribed throughout, the A ring is an unsubstituted 5-memberedheteroaryl ring. In any of the embodiments described throughout, the Aring is an optionally substituted 6-membered heteroaryl ring. In any ofthe embodiments described throughout, the A ring is a heteroaryl ringsubstituted with at least one halo. In any of the embodiments describedthroughout, the A ring is a 5-membered heteroaryl ring substituted withat least one halo.

In any of the embodiments described throughout, the A ring is optionallysubstituted isoxazolyl, pyrazolyl, oxadiazolyl or triazolyl; and L is—C(R⁸)₂— and each R⁸ is taken together with the carbon atom to whichthey are attached to form cyclopropyl.

In any of the embodiments described throughout, the A ring is optionallysubstituted isoxazolyl, pyrazolyl, oxadiazolyl or triazolyl; and R³ andR⁶ together with the carbon atoms to which they are attached form anoptionally substituted cyclopropyl ring.

In any of the embodiments described throughout, the A ring is of theformula:

wherein

X¹⁰, X¹¹ and X¹² are each S, O, N, CR¹³ or NR¹³, and X¹³ is C or N; and

each R¹³ is independently H, halo, cyano or optionally substituted C₁-C₆alkyl.

In certain embodiments, at least one of X¹, X¹¹ and X¹² is CR¹³ or NR¹³and at least one R¹³ is halo, cyano or optionally substituted C₁-C₆alkyl. In certain embodiments, at least one of X¹⁰, X¹¹ and X¹² is CR¹³or NR¹³ and at least one R¹³ is halo.

In any of the embodiments described throughout, the A ring is one of thefollowing:

wherein each ring may be optionally substituted.

In any of the embodiments described throughout, the A ring is one of thefollowing:

In any of the embodiments described throughout, the A ring is one of thefollowing:

In any of the embodiments described throughout, the A ring is one of thefollowing:

It is appreciated that certain features described herein, which are, forclarity, described in the context of separate embodiments, may also beprovided in combination in a single embodiment. Conversely, variousfeatures described herein, which are, for brevity, described in thecontext of a single embodiment, may also be provided separately or inany suitable subcombination. All combinations of the embodimentspertaining to the chemical groups represented by the variables containedwithin Formula I (and all other Formulas described herein), arespecifically embraced by herein just as if each and every combinationwas individually and explicitly recited, to the extent that suchcombinations embrace compounds that result in stable compounds (i.e.,compounds that can be isolated, characterized and tested for biologicalactivity). In addition, all subcombinations of the chemical groupslisted in the embodiments describing such variables, as well as allsubcombinations of uses and medical indications described herein, suchas those conditions or disorders mediated by receptor-interactingprotein kinase 1, are also specifically embraced herein just as if eachand every subcombination of chemical groups and subcombination of usesand medical indications was individually and explicitly recited herein.In addition, some embodiments include every combination of one or moreadditional agents disclosed herein just as if each and every combinationwas individually and explicitly recited.

In certain embodiments, a compound may be selected from those compoundsin Table 1, 2, 3 or 4. Also included within the disclosure arestereoisomers and mixtures of stereoisomers thereof. Also includedwithin the disclosure is a compound selected from Table 1, 2, 3 or 4, orpharmaceutically acceptable salt thereof.

TABLE 1 No. Structure  1

 1A

 1B

 2

 3

 4

 5

 6

 7

 7A

 7B

 8

 9

 10

 11

 11A

 11B

 12

 12A

 12B

 13

 14

 15

 16

 17

 18

 19

 20

 21

 22

 23

 24

 25

 26

 27

 28

 29

 30

 31

 32

 33

 34

 35

 36

 37

 38A

 38B

 39

 40

 41

 42

 43

 43A

 44

 45

 46

 46A

 46B

 47

 48

 49

 50

 50A

 50B

 51

 52

 53

 54A

 54B

 55

 56

 57

 58

 59

 60

 60A

 60B

 61

 62

 63

 64

 65

 66

 67A

 67B

 68A

 68B

 69A

 69B

 70A

 70B

 71A

 71B

 72

 73

 74

 75A

 75B

 76

 77

 78

 79

 80A

 80B

 81A

 81B

 82A

 82B

 83A

 83B

 84

 85

 86

 87

 88

 89A

 89B

 90A

 90B

 91

 92

 93

 94

 95

 96

 97

 98A

 98B

 99

100A

100B

101A

101B

102A

102B

103A

103B

104A

104B

105A

105B

106

107A

107B

108

109A

109B

110A

110B

111A

111B

112

113

114A

114B

115

116

117

118A

118B

119A

119B

120A

120B

121A

121B

122

123

124

125A

125B

126

127

128

129A

129B

130

131A

131B

132

133

134

135

136

137

138

139

140

141A

141B

142

143

144

145A

145B

146

147

148A

148B

149

150

151

152A

152B

153

154A

154B

155

156A

156B

157A

157B

158

159

160A

160B

161

162

163

164

165

166

167

168

169

170A

170B

171

172

173

174

175

176

177A

177B

178A

178B

179A

179B

180A

180B

181A

181B

182A

182B

183A

183B

184

185

186

187

188

189

190

191

192

193

194

195

196

197

198

199

200

201

202

203

204

205

206

207

208

209

210

211

212

213

214

215

216

217

218

219

220

221

222

223

224

225

226

227

TABLE 2 No. Structure 1

2

3

4

5

6

7

8

9

10

11

12

13

14

19

20

23

TABLE 3 No. Structure 14

15

18

20

23

24

25

26

TABLE 4 No. Structure  1

 2

 3

 4

 5

 6

 7

 8

 9

 10

 11

 12

 13

 19

 30

 32

 35

 38A

 38B

 40

 41

 42

 43

 44

 45

 46A

 46B

 49

 50A

 50B

 51

 52

 54A

 54B

 55

 56

 57

 58

 59

 60A

 60B

 61

 62

 63

 64

 66

 67A

 67B

 68A

 68B

 69A

 69B

 70A

 70B

 71A

 71B

 72

 73

 74

 75A

 75B

 76

 77

 78

 79

 80A

 80B

 81A

 81B

 82A

 82B

 83A

 83B

 84

 85

 86

 87

 88

 89A

 89B

 90A

 90B

 91

 92

 93

 94

 96

 97

 98B

100A

100B

101B

102B

103B

104B

105A

106

107B

108

109A

110B

111B

112

113

114A

115

116

117

119B

120A

121B

122

123

124

125B

126

127

128

129A

130

131A

132

133

134

135

136

137

138

139

140

141B

142

143

144

145A

146

147

148A

148B

149

150

151

152B

153

154B

155

156B

157B

158

159

160A

161

162

163

164

165

166

167

168

169

170A

171

172

173

174

175

176

177A

178A

179A

180A

181B

182B

183B

184

188

190

192

193

194

196

197

198

200

201

203

204

205

206

207

208

209

213

214

215

216

217

218

219

220

221

222

223

224

226

227

4. Treatment Methods and Uses

“Treatment” or “treating” is an approach for obtaining beneficial ordesired results including clinical results. Beneficial or desiredclinical results may include one or more of the following: a) inhibitingthe disease or condition (e.g., decreasing one or more symptomsresulting from the disease or condition, and/or diminishing the extentof the disease or condition); b) slowing or arresting the development ofone or more clinical symptoms associated with the disease or condition(e.g., stabilizing the disease or condition, preventing or delaying theworsening or progression of the disease or condition, and/or preventingor delaying the spread (e.g., metastasis) of the disease or condition);and/or c) relieving the disease, that is, causing the regression ofclinical symptoms (e.g., ameliorating the disease state, providingpartial or total remission of the disease or condition, enhancing effectof another medication, delaying the progression of the disease,increasing the quality of life, and/or prolonging survival.

“Prevention” or “preventing” means any treatment of a disease orcondition that causes the clinical symptoms of the disease or conditionnot to develop. Compounds may, in some embodiments, be administered to asubject (including a human) who is at risk or has a family history ofthe disease or condition.

“Subject” refers to an animal, such as a mammal (including a human),that has been or will be the object of treatment, observation orexperiment. The methods described herein may be useful in human therapyand/or veterinary applications. In some embodiments, the subject is amammal. In one embodiment, the subject is a human.

The term “therapeutically effective amount” or “effective amount” of acompound described herein or a pharmaceutically acceptable salt,tautomer, stereoisomer, mixture of stereoisomers, prodrug, or deuteratedanalog thereof means an amount sufficient to effect treatment whenadministered to a subject, to provide a therapeutic benefit such asamelioration of symptoms or slowing of disease progression. For example,a therapeutically effective amount may be an amount sufficient todecrease a symptom of a disease or condition of as described herein. Thetherapeutically effective amount may vary depending on the subject, anddisease or condition being treated, the weight and age of the subject,the severity of the disease or condition, and the manner ofadministering, which can readily be determined by one of ordinary skillin the art.

The term “trauma” as used herein refers to any physical damage to thebody caused by violence, accident, fracture etc. The term “ischemia”refers to a cardiovascular disorder characterized by a low oxygen stateusually due to the obstruction of the arterial blood supply orinadequate blood flow leading to hypoxia in the tissue. The term“stroke” refers to cardiovascular disorders caused by a blood clot orbleeding in the brain, most commonly caused by an interruption in theflow of blood in the brain as from clot blocking a blood vessel and incertain embodiments of the disclosure the term stroke refers to ischemicstroke or hemorrhagic stroke. The term “myocardial infarction” refers toa cardiovascular disorder characterized by localized necrosis resultingfrom obstruction of the blood supply.

The methods described herein may be applied to cell populations in vivoor ex vivo. “In vivo” means within a living individual, as within ananimal or human. In this context, the methods described herein may beused therapeutically in an individual. “Ex vivo” means outside of aliving individual. Examples of ex vivo cell populations include in vitrocell cultures and biological samples including fluid or tissue samplesobtained from individuals. Such samples may be obtained by methods wellknown in the art. Exemplary biological fluid samples include blood,cerebrospinal fluid, urine, and saliva. In this context, the compoundsand compositions described herein may be used for a variety of purposes,including therapeutic and experimental purposes. For example, thecompounds and compositions described herein may be used ex vivo todetermine the optimal schedule and/or dosing of administration of acompound of the present disclosure for a given indication, cell type,individual, and other parameters. Information gleaned from such use maybe used for experimental purposes or in the clinic to set protocols forin vivo treatment. Other ex vivo uses for which the compounds andcompositions described herein may be suited are described below or willbecome apparent to those skilled in the art. The selected compounds maybe further characterized to examine the safety or tolerance dosage inhuman or non-human subjects. Such properties may be examined usingcommonly known methods to those skilled in the art.

Experiments with knockout animal models and Necrostatin 1, areceptor-interacting protein kinase 1 inhibitor, have demonstrated theeffectiveness of receptor-interacting protein kinase 1 inhibition inprotecting tissues from inflammatory bowel diseases (e.g., ulcerativecolitis and Crohn's disease), psoriasis, retinal-detachment-inducedphotoreceptor necrosis, retinitis pigmentosa, cerulein-induced acutepancreatitis, and sepsis/systemic inflammatory response syndrome (SIRS),and alleviating ischemic brain injury, retinal ischemia/reperfusioninjury, Huntington's disease, renal ischemia reperfusion injury,cisplatin induced kidney injury, traumatic brain injury, hematologicaland solid organ malignancies, bacterial infections and viral infections(e.g., tuberculosis and influenza) and lysosomal storage diseases.

The receptor-interacting protein kinase 1 inhibitors of the presentdisclosure are therefore useful for treating diseases and conditionsmediated by receptor-interacting protein kinase 1, including but notlimited to inflammatory diseases or disorders, necrotic cell diseases,neurodegenerative diseases, central nervous system (CNS) diseases,ocular diseases, infections, and malignancies. In certain embodiments,the receptor-interacting protein kinase 1 inhibitors described hereincan inhibit inflammation, protect tissue or cell from damage orundesired cell death (e.g., necrosis or apoptosis), ameliorate symptoms,and improve immune response or neuronal function in a patient sufferingfrom any of the prescribed diseases or conditions. Moreover, thecompounds may be suitable for treatment of immune-mediated disease, suchas but not limited to, allergic diseases, autoimmune diseases, andprevention of transplant rejection.

Provided herein are compounds and compositions for use in medicine. Incertain embodiments, the compounds and compositions are for use in thetreatment of a receptor-interacting protein kinase 1-mediated disease ordisorder. Also provided is a method of treating a receptor-interactingprotein kinase 1-mediated disease or disorder comprising administering atherapeutically effective amount of a compound or pharmaceuticalcomposition disclosed herein to a subject in need thereof. In certainembodiments, the disease or disorder is an inflammatory diseaseassociated with A20 SNPs.

Various specific diseases and disorders are described below. In certainembodiments, the disease or disorder is necrotizing enterocolitis,tuberous sclerosis, Tangier's Disease, Wohlman's Syndrome, inflammatorybowel disease, Crohn's disease, ulcerative colitis, psoriasis, retinaldetachment, retinitis pigmentosa, macular degeneration, pancreatitis(e.g., acute pancreatitis), atopic dermatitis, rheumatoid arthritis,spondyloarthritis, gout, SoJIA, systemic lupus erythematosus, Sjogren'ssyndrome, systemic scleroderma, anti-phospholipid syndrome, vasculitis,osteoarthritis, non-alcohol steatohepatitis, alcohol steatohepatitis,autoimmune hepatitis autoimmune hepatobiliary diseases, primarysclerosing cholangitis, nephritis, Celiac disease, autoimmune ITP,transplant rejection, ischemia reperfusion injury of solid organs,sepsis, systemic inflammatory response syndrome, cerebrovascularaccident, myocardial infarction, Huntington's disease, Alzheimer'sdisease, Parkinson's disease, allergic diseases, asthma, atopicdermatitis, multiple sclerosis, type I diabetes, Wegener'sgranulomatosis, pulmonary sarcoidosis, Behget's disease, interleukin-1converting enzyme associated fever syndrome, chronic obstructivepulmonary disease, tumor necrosis factor receptor-associated periodicsyndrome, periodontitis, bacterial infection, staphylococcus infection,mycobacterium infection, ofretinitis pigmentosa, influenza, transplantrejection, burns or hypoxia. In certain embodiments, the disease ordisorder is trauma, ischemia, stroke, cardiac infarction, infection,lysosomal storage disease, Niemann-Pick disease, Gaucher's disease,Krabbe disease, sepsis, Parkinson's disease, Alzheimer's disease,amyotrophic lateral sclerosis (ALS/Lou Gehrig's Disease), Huntington'sdisease, HIV-associated dementia, encephalopathy, retinal degenerativedisease, glaucoma, age-related macular degeneration, rheumatoidarthritis, psoriasis, psoriatic arthritis or inflammatory bowel disease.In certain embodiments, the disease or disorder is Alzheimer's disease,ALS, Friedreich's ataxia, Huntington's disease, Lewy body disease,Parkinson's disease, Huntington's disease, multiple sclerosis, diabeticneuropathy, polyglutamine (polyQ) diseases, stroke, Fahr disease,Menke's disease, Wilson's disease, cerebral ischemia, lysosomal storagedisease or a prion disorder. In certain embodiments, the disease is ALS.In certain embodiments, the disease is Alzheimer's disease. In certainembodiments, the disease is lysosomal storage disease. In certainembodiments, the disease is Parkinson's disease. In certain embodimentsthe disorder is an ischemic disease of organs including but not limitedto brain, heart, kidney and liver. In some different embodiments, thedisorder is an ocular disorder such as retinal degenerative disease,glaucoma or age-related macular degeneration. In some differentembodiments, the disorder is a central nervous system (CNS) disorder.

In certain embodiments, the compounds and compositions are useful fortreating psoriasis.

In certain embodiments, the disorder is an inflammatory disease of theintestines such as Crohn's disease or ulcerative colitis (both generallyknown together as inflammatory bowel disease). In certain embodiments,the mammal is a primate, canine or feline subject. In certainembodiments, the mammal is a human subject. While not wishing to bebound by theory, it is believed that inhibition of receptor interactingprotein kinase 1 by the presently disclosed compounds is responsible, atleast in part, for their anti-inflammatory activity. Accordingly,embodiments of the disclosure also include methods for inhibitingreceptor interacting protein kinase 1, either in vitro or in a subjectin need thereof, the method comprises contacting a receptor interactingprotein kinase 1 with a compound disclosed herein. In some of theseembodiments, inhibiting receptor interacting protein kinase 1 iseffective to block (partially or fully) the release of inflammatorymediators such as TNF and/or IL6.

In certain embodiments, provided is a method of treating a disease ordisorder selected from the group consisting of rheumatoid arthritis,systemic onset juvenile idiopathic arthritis (SoJIA), spondyloarthritis,osteoarthritis, psoriasis, Crohn's disease, ulcerative colitis, andmultiple sclerosis, comprising administering a therapeutically effectiveamount of a compound as provided herein to a subject in need thereof. Incertain embodiments, provided is a method of treating a disease ordisorder selected from the group consisting of autoimmune hepatitis,atherosclerosis, neutrophilic dermatoses, or a rare disease driven byA20, NEMO, and/or LUBAC mutations, comprising administering atherapeutically effective amount of a compound as provided herein to asubject in need thereof. In certain embodiments, the compound is ofFormula I (or any Formula described herein or tautomer thereof), whereinA is triazole. In certain embodiments, the compound is of Formula V orVa. In certain embodiments, the method comprises administering Compound42 or tautomer thereof.

Inflammatory Diseases or Disorders

The receptor-interacting protein kinase 1 inhibitors described hereinmay be used to treat inflammatory diseases and disorders. Inflammatorydiseases and disorders typically exhibit high levels of inflammation inthe connective tissues, or degeneration of these tissues.

Non-limiting examples of inflammatory diseases and disorders includeAlzheimer's, ankylosing spondylitis, arthritis including osteoarthritis,rheumatoid arthritis (RA), psoriasis, asthma, atherosclerosis, Crohn'sdisease, colitis, dermatitis, diverticulitis, fibromyalgia, hepatitis,irritable bowel syndrome (IBS), inflammatory bowel disease (IBD),systemic lupus erythematous (SLE), nephritis, Parkinson's disease, andulcerative colitis.

In certain embodiments, the compounds and compositions of the presentdisclosure are useful for treating rheumatoid arthritis (RA). In certainembodiments, the compounds and compositions of the present disclosureare useful for treating ulcerative colitis. In certain embodiments, thecompounds and compositions of the present disclosure are useful fortreating psoriasis. In certain embodiments, the compounds andcompositions of the present disclosure are useful for treating psoriasisor psoriatic arthritis. In certain embodiments, the disease isspondyloarthritis.

Necrotic Cell Diseases

The compounds described herein may be used for the treatment ofdiseases/disorders caused or otherwise associated with necrosis. Theterm “necrotic cell disease” refers to diseases associated with orcaused by cellular necrosis, for example trauma, ischemia, stroke,cardiac infarction, infection, Gaucher's disease, Krabbe disease,sepsis, Parkinson's disease, Alzheimer's disease, amyotrophic lateralsclerosis, Huntington's disease, HIV-associated dementia, retinaldegenerative disease, glaucoma, age-related macular degeneration,rheumatoid arthritis, psoriasis, psoriatic arthritis or inflammatorybowel disease.

The necrotic cell diseases can be acute diseases such as trauma,ischemia, stroke, cardiac infarction, anthrax lethal toxin inducedseptic shock, sepsis, cell death induced by LPS, and HIV induced T-celldeath leading to immunodeficiency. The necrotic cell diseases alsoinclude chronic neurodegenerative diseases, such as Parkinson's disease,Huntington's disease, amyotrophic lateral sclerosis, Alzheimer'sdisease, infectious encelopathies, and dementia such as HIV associateddementia.

Neurodegenerative and CNS Diseases

The receptor-interacting protein kinase 1 inhibitors described hereinmay also be used to treat neurodegenerative diseases. Neurodegenerativediseases can affect many of the body's activities, such as balance,movement, talking, breathing, and heart function. Neurodegenerativediseases can be genetic or caused by medical conditions such asalcoholism, tumors, strokes, toxins, chemicals, and viruses.

Non-limiting examples of neurodegenerative diseases include Alzheimer'sdisease, amyotrophic lateral sclerosis (ALS), Friedreich's ataxia,Huntington's disease, Lewy body disease, Parkinson's disease, and spinalmuscular atrophy. In certain embodiments, neurodegenerative diseases andCNS diseases include Niemann-Pick disease, type C1 (NPC1), Alzheimer'sdisease, amyotrophic lateral sclerosis (ALS), Friedreich's ataxia,Huntington's disease, Lewy body disease, Parkinson's disease; and spinalmuscular atrophy.

In certain embodiments, the receptor interacting protein kinase 1inhibitors described herein may be used to treat NPC1 via inhibitingnecroptosis that causes neuronal loss. In certain embodiments, thecompounds and compositions of the present disclosure are useful fortreating Alzheimer's disease. In certain embodiments, the compounds andcompositions of the present disclosure are useful for treatingParkinson's disease. In certain embodiments, the compounds andcompositions of the present disclosure are useful for treatingamyotrophic lateral sclerosis (ALS).

More generally, the receptor-interacting protein kinase 1 inhibitorsdescribed herein can be used to preserve neuron viability and promoteaxon growth and nerve functions within the central nervous system (CNS).Accordingly, the compounds may be used to reduce or even reverse theloss of cognitive, motor, and sensory functions associated with a CNSdisease or disorder, by preserving neuron viability and/or promotingaxon regeneration and/or nerve functions.

The receptor-interacting protein kinase 1 inhibitors described hereincan be used in a method for promoting axon regeneration in a CNS neuron,such as a CNS sensory neuron, a motor neuron, a cortical neuron, acerebellar neuron, a hippocampal neuron, and a midbrain neuron. Thereceptor-interacting protein kinase 1 inhibitors described herein can beused in a method for promoting nerve function or preserving theviability following injury to a CNS neuron. In another embodiments,these compounds can be used to promote regeneration of an axon in a CNSneuron that is degenerated in the CNS disease or disorder. The RIPreceptor-interacting protein kinase 1 inhibitors may be administered byany conventional means, such as locally to the neuron or applied ex vivobefore re-implantation.

Accordingly, in one aspect, the disclosure provides a method of treatinga CNS disorder in a subject in need thereof, wherein a symptom of theCNS disorder is axon degeneration or injury within a CNS neuron. Themethod comprises administering to the subject an effective amount of acompound or composition disclosed herein thereby to promote regenerationof an axon in a CNS neuron affected by the CNS disorder. Followingadministration, neural functions may be measured, for example, as anindication of axon regeneration. It is also contemplated that, followingadministration of the compound or composition, the neuron function ofthe CNS neuron is preserved or improved relative to the neuron functionprior to administration.

Non-limiting examples of CNS diseases or disorders include brain injury,spinal cord injury, dementia, stroke, Alzheimer's disease, amyotrophiclateral sclerosis (ALS/Lou Gehrig's Disease), Parkinson's disease,Huntington's disease, multiple sclerosis, diabetic neuropathy,polyglutamine (polyQ) diseases, stroke, Fahr disease, Menke's disease,Wilson's disease, cerebral ischemia, and a prion disorder.

In exemplary embodiments, the CNS disorder is brain injury or spinalcord injury.

Also provided herein are methods for promoting neuron survival and axonregeneration in the CNS. CNS disorders characterized by impaired orfailing axon growth or axon degeneration may arise from CNS neuroninjury (e.g., trauma, surgery, nerve compression, nerve contusion, nervetransection, neurotoxicity or other physical injury to the brain orspinal cord) or neurodegenerative CNS disease, wherein a symptom of thedisorder is axon degeneration (e.g., Alzheimer's disease, amyotrophiclateral sclerosis (ALS/Lou Gehrig's Disease), Parkinson's disease,multiple sclerosis, diabetic neuropathy, polyglutamine (polyQ) diseases,stroke, Fahr disease, Menke's disease, Wilson's disease, cerebralischemia, prion disorder (e.g., Creutzfeldt-Jakob disease). In certainembodiments, the CNS disorder is brain injury (e.g., traumatic braininjury) or spinal cord injury (e.g., chronic, acute or traumatic spinalcord injury). In certain embodiments, the CNS disorder affects asubject's basic vital life functions such as breathing, heart beat andblood pressure, e.g., an injury to or aneurysm in the brain stem.

In certain embodiments, the CNS disease or disorder affects a subject'scognitive ability. In certain embodiments, the CNS disease or disorderaffects a subject's movement and/or strength. In certain embodiments,the CNS disease or disorder affects a subject's coordination.

In certain embodiments, the CNS disorder affects a subject's cognitiveability, such as, brain injury to the cerebral cortex or aneurodegenerative CNS disorder, such as, Alzheimer's disease,frontotemporal dementia, dementia with Lewy bodies, corticobasaldegeneration, progressive supranuclear palsy and prion disorders.

In certain embodiments, the CNS disorder affects a subject's movementand/or strength, such as injury to the brain or spinal cord or aneurodegenerative CNS disorder such as Parkinson's disease,frontotemporal dementia, dementia with Lewy bodies, corticobasaldegeneration, progress supranuclear palsy, Huntington's disease,multiple system atrophy, amyotrophic lateral sclerosis and hereditaryspastic paresis.

In certain embodiments, the CNS disorder affects a subject'scoordination, such as brain injury to the cerebellum or aneurodegenerative CNS disorder such as spinocerebellar atrophies,Friedreich's ataxia and prion disorders.

In each of the foregoing methods, the CNS disorder includes, but is notlimited to, brain injury, spinal cord injury, Alzheimer's disease,amyotrophic lateral sclerosis (ALS/Lou Gehrig's Disease), Parkinson'sdisease, multiple sclerosis, diabetic neuropathy, polyglutamine (polyQ)diseases, stroke, Fahr disease, Menke's disease, Wilson's disease,cerebral ischemia, a prion disorder (e.g., Creutzfeldt-Jakob disease),dementia (e.g., frontotemporal dementia, dementia with Lewy bodies),corticobasal degeneration, progressive supranuclear palsy, multiplesystem atrophy, hereditary spastic paraparesis and spinocerebellaratrophies.

Non-limiting examples of neurodegenerative diseases include Alzheimer'sdisease, lysomal storage diseases, amyotrophic lateral sclerosis (ALS),Friedreich's ataxia, Huntington's disease, Lewy body disease,Parkinson's disease, and spinal muscular atrophy.

In certain embodiments, the compounds and compositions of the presentdisclosure are useful for treating Alzheimer's disease. In certainembodiments, the compounds and compositions of the present disclosureare useful for treating Parkinson's disease. In certain embodiments, thecompounds and compositions of the present disclosure are useful fortreating amyotrophic lateral sclerosis (ALS). In certain embodiments,the compounds and compositions of the present disclosure are useful fortreating lysosomal storage diseases.

In certain embodiments, the disorder is a brain disorders, such as, butnot limited to, Alzheimer's disease, ALS, frontotemporal dementias,vascular dementia, Huntington's disease, Parkinson's disease, Lewy Bodydementia, Progressive Supranuclear Palsy, multiple sclerosis,neuromyelitis optica, ischemic brain damage (stroke), hypoxic braindamage, traumatic brain injury, spinal cord injury, sepsis-induced braindamage, CNS infections, CNS abscesses, glioblastoma multiforme,epilepsy, neuropathic pain, major depression, bipolar depression,schizophrenia, autism, Niemann-Pick disease, neuro-Behget's disease.

In certain embodiments, provided is a method of treating a CNS diseaseor disorder, comprising administering a therapeutically effective amountof a compound as provided herein to a subject in need thereof. Incertain embodiments, the disease or disorder is Alzheimer's disease oramyotrophic lateral sclerosis (ALS). In certain embodiments, thecompound is of Formula I (or any Formula described herein), wherein A isother than triazole. In certain embodiments, the compound is of FormulaVI.

Ocular Conditions

The receptor-interacting protein kinase 1 inhibitors described hereincan also be used to treat ocular conditions, for example to reduce orprevent the loss of photoreceptor and/or retinal pigment epithelial cellviability.

In certain embodiments, the disclosure provides a method of preservingthe visual function of an eye of a subject with an ocular condition,wherein a symptom of the ocular condition is the loss of photoreceptorcell viability in the retina of the eye with the condition. The methodcomprises administering to the eye of the subject an effective amount ofa compound or composition described herein, thereby preserving theviability of the photoreceptor cells disposed within the retina of theeye. After administration, the visual function (e.g., visual acuity) ofthe eye may be preserved or improved relative to the visual function ofthe eye prior to administration.

The ocular condition may be a condition selected from the groupconsisting of age-related macular degeneration (AMD), retinosispigmentosa (RP), macular edema, diabetic retinopathy, central areolarchoroidal dystrophy, BEST disease, adult vitelliform disease, patterndystrophy, myopic degeneration, central serous retinopathy, Stargardt'sdisease, Cone-Rod dystrophy, North Carolina dystrophy, infectiousretinitis, inflammatory retinitis, uveitis, toxic retinitis andlight-induced toxicity. AMD may be the neovascular or the dry form ofAMD. Retinal detachment may be a rhegmatogenous, a serous, and atractional retinal detachment. In certain embodiments, the ocularcondition may be a condition selected from the group consisting ofgeographic atrophy, glaucoma, and other ischemic eye diseases.

In certain embodiments, the disclosure provides a method of preservingthe viability of retinal pigment epithelial (RPE) cells within theretina of a subject with an ocular condition with administration of acompound of the present disclosure. The subject being treated may have aloss of retinal pigment epithelial cells in the retina of the eye withthe condition and the ocular condition may be selected from the groupconsisting of age-related macular degeneration (AMD), BEST disease,myopic degeneration, Stargardt's disease, uveitis, adult foveomaculardystrophy, fundus falvimaculatus, multiple evanescent white dotsyndrome, serpiginous choroidopathy, acute multifocal posterior placoidepitheliopathy (AMPPE), and other uveitis disorders. In certainembodiments, the method comprises administering to the eye of thesubject an effective amount of a compound or composition describedherein, thereby preserving the viability of the retinal pigmentepithelial cells.

Provided in another embodiment is a method of preserving the viabilityof photoreceptor cells disposed within a retina of a subject with anocular condition selected from the group consisting of age-relatedmacular degeneration (AMD), retinosis pigmentosa (RP), macular edema,diabetic retinopathy, central areolar choroidal dystrophy, BEST disease,adult vitelliform disease, pattern dystrophy, myopic degeneration,central serous retinopathy, Stargardt's disease, Cone-Rod dystrophy,North Carolina dystrophy, infectious retinitis, inflammatory retinitis,uveitis, toxic retinitis and light-induced toxicity. Therefore, incertain embodiments, the method comprises administering to the eye aneffective amount of a compound or composition described herein, therebypreserving the viability of the photoreceptor cells disposed within theretina of the subject with a condition.

Provided in another embodiment is a method of preserving the viabilityof photoreceptor cells disposed within a retina of a mammalian eyefollowing retinal detachment. The retinal detachment may be arhegmatogenous retinal detachment, tractional retinal detachment, orserous retinal detachment. In other embodiments, the retinal detachmentmay occur as a result of a retinal tear, retinoblastoma, melanoma orother cancers, diabetic retinopathy, uveitis, choroidalneovascularization, retinal ischemia, pathologic myopia, or trauma. Incertain embodiments, the method comprises administering a compound orcomposition described herein to the eye in which a region of the retinahas been detached in amounts sufficient to preserve the viability ofphotoreceptor cells disposed within the region of the detached retina.

Provided in another embodiment is a method of preserving visual functionof an eye of a subject with an ocular condition selected from the groupconsisting of age-related macular degeneration (AMD), retinosispigmentosa (RP), macular edema, central areolar choroidal dystrophy,retinal detachment, diabetic retinopathy, BEST disease, adultvitelliform disease, pattern dystrophy, myopic degeneration, centralserous retinopathy, Stargardt's disease, Cone-Rod dystrophy, NorthCarolina dystrophy, infectious retinitis, inflammatory retinitis,uveitis, toxic retinitis and light-induced toxicity, wherein a symptomof the ocular condition is the loss of photoreceptor cells viability inthe retina of the eye, wherein the method comprises treating the subjectwith a compound or composition described herein to the subject.

In another aspect, the disclosure provides a method of preserving thevisual function of an eye of a subject with an ocular condition, whereina symptom of the ocular condition is the loss of photoreceptor cellviability and/or RPE viability in the retina of the eye wherein themethod comprises treating the subject with a compound or compositiondescribed herein to the subject.

In certain embodiments, provided a method of preserving the visualfunction of an eye of a subject with ocular conditions, wherein asymptom of the ocular condition is the loss of retinal ganglion cellviability in the retina of the eye with the conditions. The methodcomprises administering to the eye of the subject an effective amount ofa compound or composition, thereby preserving the viability of theretinal ganglion cells disposed within the retina of the eye. Afteradministration of the compound or composition, the visual function ofthe eye may be preserved or improved relative to the visual function ofthe eye prior to administration. Further, after the administration, thepreserved retinal ganglion cell is capable of supporting axonalregeneration.

Non-limiting examples of symptoms associated with the ocular conditionsinclude the loss of retinal ganglion cell viability in the retina of theeye, glaucoma, optic nerve injury, optic neuritis, optic neuropathies,diabetic retinopathy, central retinal artery occlusion, and centralretinal vein occlusion.

The compounds described herein may also be used for the treatment ofoptic neuropathies such as ischemic optic neuropathy (e.g., arteritic ornon-arteritic anterior ischemic neuropathy and posterior ischemic opticneuropathy), compressive optic neuropathy, infiltrative opticneuropathy, traumatic optic neuropathy, mitochondrial optic neuropathy(e.g., Leber's optic neuropathy), nutritional optic neuropathy, toxicoptic neuropathy, and hereditary optic neuropathy (e.g., Leber's opticneuropathy, Dominant Optic Atrophy, Behr's syndrome).

Also disclosed is a method of preserving the visual function of an eyeof a subject with an ocular condition selected from the group consistingof glaucoma, optic nerve injury, optic neuropathies, diabeticretinopathy, central retinal artery occlusion and central retinal veinocclusion. The method comprises administering to the eye of the subjectan effective amount of a compound or composition described herein,thereby preserving the viability of the retinal ganglion cells disposedwithin the retina of the eye and the visual function of the eye.

In another aspect, disclosed herein is a method of preserving theviability of retinal ganglion cells disposed within a retina of amammalian eye affected by, for example, glaucoma, optic nerve injury,optic neuritis, optic neuropathies, diabetic retinopathy, centralretinal artery occlusion and central retinal vein occlusion. The methodcomprises administering a compound or composition described herein tothe eye in which a region of the retina has been affected in amountssufficient to preserve the viability of retinal ganglion cells disposedwithin the region of the affected retina. The preserved retinal ganglioncell is capable of supporting axonal regeneration.

Also disclosed is a method for promoting axon regeneration in an eye ofa subject with an ocular condition, wherein a symptom of the ocularcondition is the loss of retinal ganglion cell viability in the retinaof the eye with the condition. The method comprises administering to theeye of the subject an effective amount of a compound or compositiondescribed herein, thereby promoting axon regeneration of the retinalganglion cell within the retina of the eye.

In each of the foregoing embodiments, it is understood that the methodsand compositions described herein can be used to preserve the viabilityand/or promote axon regeneration of retinal ganglion cells duringtreatment of the underlying conditions including, but not limited to,glaucoma, optic nerve injury, optic neuritis, optic neuropathies,diabetic retinopathy, central retinal artery occlusion and centralretinal vein occlusion.

Tissue Injuries or Damages

The ability of the compounds described herein to inhibit inflammationand cell death makes them suitable for ameliorating tissue injuries ordamages. The tissue injuries or damages may be a result of any of thediseases or conditions described above. For example, the compounds maybe used for amelioration of brain tissue injury or damage followingischemic brain injury or traumatic brain injury, or for amelioration ofheart tissue injury or damage following myocardial infarction, or foramelioration of brain tissue injury or damage associated withHuntington's disease, Alzheimer's disease or Parkinson's disease, or foramelioration of liver tissue injury or damage associated withnon-alcohol steatohepatitis, alcohol steatohepatitis, autoimmunehepatitis autoimmune hepatobiliary diseases, or primary sclerosingcholangitis, or for the amelioration of liver tissue injury or damageassociated with overdose of acetaminophen, or for amelioration of kidneytissue injury or damage following renal transplant or the administrationof nephrotoxic drugs or substances. In certain embodiments, the Forexample, the compounds may be used for amelioration of brain tissueinjury or damage following pulmonary injury or damage.

Non-limiting examples of brain injury or damage include stroke (e.g.,hemorrhagic and non-hemorrhagic), traumatic brain injury (TBI), cerebralhemorrhage, subarachnoid hemorrhage, intracranial hemorrhage secondaryto cerebral arterial malformation, cerebral infarction, perinatal braininjury, non-traumatic brain injury, Alzheimer's disease, Parkinson'sdisease, Huntington's disease, multiple sclerosis, amyotrophic lateralsclerosis, brain hemorrhage, brain infections, brain tumor, subclinicalbrain injury, spinal cord injury, anoxic-ischemic brain injury, focalcerebral ischemia, global cerebral ischemia, and hypoxic hypoxia.

In an embodiment, the compounds and compositions of the presentdisclosure may be used to treat peritoneal tissue injury. Non-limitingexamples of peritoneal tissue injury include peritoneal deterioration,peritoneal sclerosis, and peritoneal cancer. For example, the receptorinteracting protein kinase 1 inhibitors described herein may be used totreat peritoneal damage caused by peritoneal dialysis fluid (PDF) andPD-related side effects.

Liver Injury and Diseases

In an embodiment, the compounds and compositions of the presentdisclosure may be used to treat liver injury and diseases. Non-limitingexamples of liver injury or damage include not only degeneration ornecrosis of liver parenchyma cells which results from injury caused by acertain factor, but also undesirable phenomena caused by biologicalreactions to the injury, such as mobilization, infiltration, activationof Kupffer cells, leukocytes and the like, fibrosis of the liver tissue,etc., which reactions occur alone or in combination. In certainembodiments, the receptor interacting protein kinase 1 inhibitorsdescribed herein may be used to treat steatohepatitis and hepatocellularcarcinoma via inhibiting receptor interacting protein kinase 1activity-dependent apoptosis of hepatocytes and hepatocarcinogenesis. Inan embodiment, the receptor interacting protein kinase 1 inhibitorsdescribed herein may be used to treat alcoholic hepatitis, autoimmunehepatitis, fulminent hepatic failure, acute cholestasis and liverinjury.

Kidney Injury and Diseases

In an embodiment, the compounds and compositions of the presentdisclosure may be used to treat kidney injury and diseases. Non-limitingexamples of kidney diseases include chronic kidney disease (CKD) (e.g.,glomerular diseases, tubulointerstitial diseases, obstruction,polycystic kidney disease), acute kidney injury (AKI), diabeticnephropathy, fibrosis, glomerulonephritis, focal glomerulosclerosis,immune complex nephropathy, crystalline nephropathy, or lupus nephritis.Kidney disease may be caused by drug-induced renal injury or kidneygraft rejection. Kidney disease may be characterized as nephroticsyndrome or renal insufficiency. In an embodiment, the receptorinteracting protein kinase 1 inhibitors described herein may be used totreat kidney diseases (e.g., AKI) via inhibiting cell death pathway inkidney diseases. In an embodiment, the receptor interacting proteinkinase 1 inhibitors described herein may be used to treat patient withkidney stones and to prevent crystal-induced cytotoxicity and acutekidney injury via inhibiting receptor interacting protein kinase3-MLKL-mediated necroptosis.

Skin Diseases

In an embodiment, the compounds and compositions of the presentdisclosure may be used to treat dermal (or skin) diseases, including butnot limited to, inflammatory skin diseases or neutrophilic dermatosis.

Malignancies

In an embodiment, the compounds and compositions of the presentdisclosure are useful for treating malignancies/cancers such ascarcinoma, sarcoma, melanoma, lymphoma or leukemia. Non-limitingexamples of malignancies suitably treated by the receptor interactingprotein kinase 1 inhibitors described herein include lung cancer (e.g.non-small cell lung cancer, small-cell lung cancer), hepatocellularcancer, melanoma, pancreatic cancer, urological cancer, bladder cancer,colorectal cancer, colon cancer, breast cancer, prostate cancer, renalcancer, thyroid cancer, gall bladder cancer, peritoneal cancer, ovariancancer, cervical cancer, gastric cancer, endometrial cancer, esophagealcancer, head and neck cancer, neuroendocrine cancer, CNS cancer, braintumors (e.g., glioma, anaplastic oligodendroglioma, adult glioblastomamultiforme, and adult anaplastic astrocytoma), bone cancer, soft tissuesarcoma, retinoblastomas, neuroblastomas, peritoneal effusions,malignant pleural effusions, mesotheliomas, Wilms tumors, trophoblasticneoplasms, hemangiopericytomas, Kaposi's sarcomas, myxoid carcinoma,round cell carcinoma, squamous cell carcinomas, esophageal squamous cellcarcinomas, oral carcinomas, vulval cancer, cancers of the adrenalcortex, ACTH producing tumors, lymphoma, and leukemia.

Infectious Diseases

In an embodiment, the compounds and compositions of the presentdisclosure are useful for treating infectious diseases resulting fromthe presence of pathogenic agents, including pathogenic viruses,pathogenic bacteria, fungi, protozoa, multicellular parasites andaberrant proteins known as prions. Non-limiting examples of infectiousdiseases suitably treated by the receptor interacting protein kinase 1inhibitors described herein include virus infectious diseases andbacterial infectious diseases. The virus infectious disease is notparticularly limited and includes, for example, infectious diseases withrespiratory infectious viruses (e.g., infectious diseases due torespiratory infectious viruses such as influenza virus, rhino virus,corona virus, parainfluenza virus, RS virus, adeno virus, reo virus andthe like), Staphylococcus aureus (MRSA) pneumonia, Serratia marcescenshemorrhagic pneumonia, herpes zoster caused by herpes virus, diarrheacaused by rotavirus, viral hepatitis, AIDS and the like. The bacterialinfectious disease is not particularly limited and includes, forexample, infectious diseases caused by Bacillus cereus, Vibrioparahaemolyticus, Enterohemorrhagic Escherichia coli, Staphylococcusaureus, MRSA, Salmonella, Botulinus, Candida and the like.

Bone Diseases

In an embodiment, the compounds and compositions of the presentdisclosure are useful for treating bone diseases that may result from abone remodeling disorder whereby the balance between bone formation andbone resorption is shifted. Non-limiting examples of bone remodelingdisorders include osteoporosis, Paget's disease, osteoarthritis,rheumatoid arthritis, achondroplasia, osteochodrytis,hyperparathyroidism, osteogenesis imperfecta, congenitalhypophosphatasia, fribromatous lesions, fibrous displasia, multiplemyeloma, abnormal bone turnover, osteolytic bone disease and periodontaldisease. Additional examples of bone diseases suitably treated by thereceptor interacting protein kinase 1 inhibitors described hereininclude bone fracture, bone trauma, or a bone deficit conditionassociated with post-traumatic bone surgery, post-prosthetic jointsurgery, post-plastic bone surgery, post-dental surgery, bonechemotherapy treatment or bone radiotherapy treatment. Additionalexamples of diseases affecting bone or bone joints suitably treated bythe receptor interacting protein kinase 1 inhibitors described hereininclude metastatic bone cancer, rheumatic diseases such as rheumatoidarthritis, osteoarthritis and other inflammatory arthropathies. In anembodiment, the receptor interacting protein kinase 1 inhibitorsdescribed herein may be used to treat postmenopausal osteoporosis viainhibiting osteocyte necroptosis and trabecular deterioration.

Cardiovascular Diseases

In an embodiment, the compounds and compositions of the presentdisclosure are useful for treating cardiovascular diseases that may berelate to the cardiovascular disorders of fragile plaque disorder,occlusive disorder and stenosis. Non-limiting cardiovascular diseasesinclude coronary artery disorders and peripheral arterial disorders,including, among others, atherosclerosis, arterial occlusion, aneurysmformation, thrombosis, post-traumatic aneurysm formation, restenosis,and post-operative graft occlusion. It is believed that atherosclerosisresults from maladaptive inflammation driven primarily by macrophages.Thus, the compounds and compositions of the present disclosure may beused to treat atherosclerosis via inhibiting macrophage necroptosis.

Transplantation

In an embodiment, the compounds and compositions of the presentdisclosure are useful for treating transplant patients. Non-limitingexamples of transplant patient suitably treated by the receptorinteracting protein kinase 1 inhibitors described herein includepatients with solid and non-solid organ and tissue transplantations andtransplants, such as liver, heart, kidney, and heterologous andautologous bone marrow transplantations/transplants. Typically,immunosuppressive therapy is used to avoid graft rejection in recipientsof solid organ transplants. Recipients of bone marrow transplants areusually subjected to extensive irradiation and chemotherapy prior totransplantation. It is believed that receptor interacting protein kinase1 and NF-κB signaling in dying cells determines cross-priming of CD8⁺ Tcells. Thus, the receptor interacting protein kinase 1 inhibitorsdescribed herein may be used to treat transplant patient and avoid graftrejection by modulating cross-priming of CD8⁺ T cells.

Other Diseases and Conditions

Additional examples of diseases and disorders suitably treated by thereceptor-interacting protein kinase 1 inhibitors described hereininclude pancreatitis, atopic dermatitis, spondyloarthritis, gout,systemic onset juvenile idiopathic arthritis (SoJIA), systemic lupuserythematosus (SLE), Sjogren's syndrome, systemic scleroderma,anti-phospholipid syndrome (APS), vasculitis, primary sclerosingcholangitis (PSC), acetaminophen toxicity, kidney damage/injury(nephritis, renal transplant, surgery, administration of nephrotoxicdrugs e.g. cisplatin, acute kidney injury(AKI)), Celiac disease,autoimmune idiopathic thrombocytopenic purpura (autoimmune ITP),cerebrovascular accident (CVA, stroke), myocardial infarction (MI),allergic diseases (including asthma), diabetes, Wegener'sgranulomatosis, pulmonary sarcoidosis, Behget's disease, interleukin-1converting enzyme (ICE/caspase-1) associated fever syndrome, chronicobstructive pulmonary disease (COPD), tumor necrosis factorreceptor-associated periodic syndrome (TRAPS), peridontitis,NEMO-deficiency syndrome (F-kappa-B essential modulator gene (also knownas IKK gamma or IKKG) deficiency syndrome), HOIL-1 deficiency ((alsoknown as RBCKl) heme-oxidized IRP2 ubiquitin ligase-1 deficiency),linear ubiquitin chain assembly complex (LUBAC) deficiency syndrome,hematological and solid organ malignancies, bacterial infections andviral infections (e.g., tuberculosis and influenza), and lysosomalstorage diseases. Additional examples of diseases and disorders suitablytreated by the receptor-interacting protein kinase 1 inhibitorsdescribed herein include Gaucher disease or organ failure.

Non-limiting examples of lysosomal storage diseases include Gaucherdisease, GM2 Gangliosidosis, alpha-mannosidosis, aspartylglucosaminuria,cholesteryl ester storage disease, chronic hexosaminidase A deficiency,cystinosis, Danon disease, Fabry disease, Farber disease, fucosidosis,galactosialidosis, GM1 gangliosidosis, mucolipidosis, infantile freesialic acid storage disease, juvenile hexosaminidase A deficiency,Krabbe disease, lysosomal acid lipase deficiency, metachromaticleukodystrophy, mucopolysaccharidoses disorders, multiple sulfatasedeficiency, Niemann-Pick disease, neuronal ceroid lipofuscinoses, Pompedisease, pycnodysostosis, Sandhoff disease, Schindler disease, sialicacid storage disease, Tay-Sachs and Wolman disease.

5. Kits

Provided herein are also kits that include a compound of the disclosure,or a pharmaceutically acceptable salt, tautomer, stereoisomer, mixtureof stereoisomers, prodrug, or deuterated analog thereof, and suitablepackaging. In certain embodiments, a kit further includes instructionsfor use. In one aspect, a kit includes a compound of the disclosure, ora pharmaceutically acceptable salt, tautomer, stereoisomer, mixture ofstereoisomers, prodrug, or deuterated analog thereof, and a label and/orinstructions for use of the compounds in the treatment of theindications, including the diseases or conditions, described herein.

Provided herein are also articles of manufacture that include a compounddescribed herein or a pharmaceutically acceptable salt, tautomer,stereoisomer, mixture of stereoisomers, prodrug, or deuterated analogthereof in a suitable container. The container may be a vial, jar,ampoule, preloaded syringe, and intravenous bag.

6. Pharmaceutical Compositions and Modes of Administration

Compounds provided herein are usually administered in the form ofpharmaceutical compositions. Thus, provided herein are alsopharmaceutical compositions that contain one or more of the compoundsdescribed herein or a pharmaceutically acceptable salt, tautomer,stereoisomer, mixture of stereoisomers, prodrug, or deuterated analogthereof and one or more pharmaceutically acceptable vehicles selectedfrom carriers, adjuvants and excipients. Suitable pharmaceuticallyacceptable vehicles may include, for example, inert solid diluents andfillers, diluents, including sterile aqueous solution and variousorganic solvents, permeation enhancers, solubilizers and adjuvants. Suchcompositions are prepared in a manner well known in the pharmaceuticalart. See, e.g., Remington's Pharmaceutical Sciences, Mace PublishingCo., Philadelphia, Pa. 17th Ed. (1985); and Modern Pharmaceutics, MarcelDekker, Inc. 3rd Ed. (G. S. Banker & C. T. Rhodes, Eds.).

The pharmaceutical compositions may be administered in either single ormultiple doses. The pharmaceutical composition may be administered byvarious methods including, for example, rectal, buccal, intranasal andtransdermal routes. In certain embodiments, the pharmaceuticalcomposition may be administered by intra-arterial injection,intravenously, intraperitoneally, parenterally, intramuscularly,subcutaneously, orally, topically, or as an inhalant.

One mode for administration is parenteral, for example, by injection.The forms in which the pharmaceutical compositions described herein maybe incorporated for administration by injection include, for example,aqueous or oil suspensions, or emulsions, with sesame oil, corn oil,cottonseed oil, or peanut oil, as well as elixirs, mannitol, dextrose,or a sterile aqueous solution, and similar pharmaceutical vehicles.

Oral administration may be another route for administration of thecompounds described herein. Administration may be via, for example,capsule or enteric coated tablets. In making the pharmaceuticalcompositions that include at least one compound described herein or apharmaceutically acceptable salt, tautomer, stereoisomer, mixture ofstereoisomers, prodrug, or deuterated analog thereof, the activeingredient is usually diluted by an excipient and/or enclosed withinsuch a carrier that can be in the form of a capsule, sachet, paper orother container. When the excipient serves as a diluent, it can be inthe form of a solid, semi-solid, or liquid material, which acts as avehicle, carrier or medium for the active ingredient. Thus, thecompositions can be in the form of tablets, pills, powders, lozenges,sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups,aerosols (as a solid or in a liquid medium), ointments containing, forexample, up to 10% by weight of the active compound, soft and hardgelatin capsules, sterile injectable solutions, and sterile packagedpowders.

Some examples of suitable excipients include lactose, dextrose, sucrose,sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates,tragacanth, gelatin, calcium silicate, microcrystalline cellulose,polyvinylpyrrolidone, cellulose, sterile water, syrup, and methylcellulose. The formulations can additionally include lubricating agentssuch as talc, magnesium stearate, and mineral oil; wetting agents;emulsifying and suspending agents; preserving agents such as methyl andpropylhydroxy-benzoates; sweetening agents; and flavoring agents.

The compositions that include at least one compound described herein ora pharmaceutically acceptable salt, tautomer, stereoisomer, mixture ofstereoisomers, prodrug, or deuterated analog thereof can be formulatedso as to provide quick, sustained or delayed release of the activeingredient after administration to the subject by employing proceduresknown in the art. Controlled release drug delivery systems for oraladministration include osmotic pump systems and dissolutional systemscontaining polymer-coated reservoirs or drug-polymer matrixformulations. Another formulation for use in the methods disclosedherein employ transdermal delivery devices (“patches”). Such transdermalpatches may be used to provide continuous or discontinuous infusion ofthe compounds described herein in controlled amounts and may beconstructed for continuous, pulsatile, or on demand delivery ofpharmaceutical agents.

For preparing solid compositions such as tablets, the principal activeingredient may be mixed with a pharmaceutical excipient to form a solidpreformulation composition containing a homogeneous mixture of acompound described herein or a pharmaceutically acceptable salt,tautomer, stereoisomer, mixture of stereoisomers, prodrug, or deuteratedanalog thereof. When referring to these preformulation compositions ashomogeneous, the active ingredient may be dispersed evenly throughoutthe composition so that the composition may be readily subdivided intoequally effective unit dosage forms such as tablets, pills and capsules.

The tablets or pills of the compounds described herein may be coated orotherwise compounded to provide a dosage form affording the advantage ofprolonged action, or to protect from the acid conditions of the stomach.For example, the tablet or pill can include an inner dosage and an outerdosage component, the latter being in the form of an envelope over theformer. The two components can be separated by an enteric layer thatserves to resist disintegration in the stomach and permit the innercomponent to pass intact into the duodenum or to be delayed in release.A variety of materials can be used for such enteric layers or coatings,such materials including a number of polymeric acids and mixtures ofpolymeric acids with such materials as shellac, cetyl alcohol, andcellulose acetate.

Compositions for inhalation or insufflation may include solutions andsuspensions in pharmaceutically acceptable, aqueous or organic solvents,or mixtures thereof, and powders. The liquid or solid compositions maycontain suitable pharmaceutically acceptable excipients as describedherein. In certain embodiments, the compositions are administered by theoral or nasal respiratory route for local or systemic effect. In otherembodiments, compositions in pharmaceutically acceptable solvents may benebulized by use of inert gases. Nebulized solutions may be inhaleddirectly from the nebulizing device or the nebulizing device may beattached to a facemask tent, or intermittent positive pressure breathingmachine. Solution, suspension, or powder compositions may beadministered, preferably orally or nasally, from devices that deliverthe formulation in an appropriate manner.

7. Combination Therapy

In certain embodiments, the compounds described herein may beadministered in combination with at least one other therapeuticallyactive agent. The two or more agents can be coadministered,co-formulated, or administered separately. In certain embodiments, theother therapeutically active agent is selected from a thrombolyticagent, a tissue plasminogen activator, an anticoagulant, a plateletaggregation inhibitor, an antimicrobial agent (an antibiotic, abroad-spectrum antibiotic, a lactam, an antimycobacterial agent, abactericidal antibiotic, anti-MRSA therapy), a long acting beta agonist,a combination of an inhaled corticosteroid and a long acting betaagonist, a short acting beta agonist, a leukotriene modifier, ananti-IgE, a methylxanthine bronchodilator, a mast cell inhibitor, aprotein tyrosine kinase inhibitor, a CRTH2/Dprostanoid receptorantagonist, an epinephrine inhalation aerosol, a phosphodiesteraseinhibitor, a combination of a phosphodiesterase-3 inhibitor and aphosphodiesterase-4 inhibitor, a long-acting inhaled anticholinergic, amuscarinic antagonist, a long-acting muscarinic antagonist, a low dosesteroid, an inhaled corticosteroid, an oral corticosteroid, a topicalcorticosteroid, anti-thymocyte globulin, thalidomide, chlorambucil, acalcium channel blocker, a topical emollient, an ACE inhibitor, aserotonin reuptake inhibitor, an endothelin-1 receptor inhibitor, ananti-fibrotic agent, a proton-pump inhibitor, a cystic fibrosistransmembrane conductance regulator potentiator, a mucolytic agent,pancreatic enzymes, a bronchodilator, an opthalmalic intravitrealinjection, an anti-vascular endothelial growth factor inhibitor, aciliary neurotrophic growth factor agent, a trivalent (IIV3) inactivatedinfluenza vaccine, a quadrivalent (IIV4) inactivated influenza vaccine,a trivalent recombinant influenza vaccine, a quadrivalent liveattenuated influenza vaccine, an antiviral agent, inactivated influenzavaccine, a ciliary neurotrophic growth factor, a gene transfer agent, atopical immunomodulator, calcineurin inhibitor, an interferon gamma, anantihistamine, a monoclonal antibody, a polyclonal anti-T-cell antibody,an anti-thymocyte gamma globulin-equine antibody, an antithymocyteglobulin-rabbit antibody, an anti-CD40 antagonist, a JAK inhibitor, andan anti-TCR murine mAb.

Exemplary other therapeutically active agents include heparin, coumadin,clopidrogel, dipyridamole, ticlopidine HCL, eptifibatide, aspirin,vacomycin, cefeprime, a combination of piperacillin and tazobactam,imipenem, meropenem, doripenem, ciprofloxacin, levofloxacin, ofloxacin,moxifloxacin, hydrocortisone, vedolizumab, alicaforsen, remestemcel-L,ixekizumab, tildrakizumab, secukinumab, chlorhexidine, doxycycline,minocycline, fluticasone (fluticasone proprionate, fluticasone furoate),beclomethasone dipropionate, budesonide, trimcinolone acetonide,flunisolide, mometasone fuorate, ciclesonide, arformoterol tartrate,formoterol fumarate, salmeterol xinafoate, albuterol (albuterolsulfate), levalbuterol tartrate, ipratropium bromide, montelukastsodium, zafirlukast, zileuton, omalizumab, theophylline, cromulynsodium, nedocromil sodium, masitinib, AMG 853, indacaterol, E004,reslizumab, salbutamol, tiotropium bromide, VR506, lebrikizumab, RPL554,afibercept, umeclidinium, indacterol maleate, aclidinium bromide,roflumilast, SCH527123, glycoprronium bromide, olodaterol, a combinationof fluticasone furoate and vilanterol vilanterol, a combination offluticasone propionate and salmeterol, a combination of fluticasonefuroate and fluticasone proprionate, a combination of fluticasonepropionate and eformoterol fumarate dihydrate, a combination offormoterol and budesonide, a combination of beclomethasone dipropionateand formoterol, a combination of mometasone furoate and formoterolfumarate dihydrate, a combination of umeclidinium and vilanterol, acombination of ipratropium bromide and albuterol sulfate, a combinationof glycopyrronium bromide and indacaterol maleate, a combination ofglycopyrrolate and formoterol fumarate, a combination of aclidinium andformoterol, isoniazid, ehambutol, rifampin, pyrazinamide, rifabutin,rifapentine, capreomycin, levofloxacin, moxifloxicin, ofloxacin,ehionamide, cycloserine, kanamycin, streptomycin, viomycin, bedaquilinefumarate, PNU-100480, delamanid, imatinib, ARG201, tocilizumab,muromonab-CD3, basiliximab, daclizumab, rituximab, prednisolone,anti-thymocyte globulin, FK506 (tacrolimus), methotrexate, cyclosporine,sirolimus, everolimus, mycophenolate sodium, mycophenolate mofetil,cyclophosphamide, azathioprine, thalidomide, chlorambucil, nifedipine,nicardipine, nitroglycerin, lisinopril, diltaizem, fluoxetine, bosentan,epoprostenol, colchicine, para-aminobenzoic acid, dimethyl sulfoxide,D-penicillamine, interferon alpha, interferon gamma (INF-g)),omeprazole, metoclopramide, lansoprazole, esomeprazole, pantoprazole,rabeprazole, imatinib, belimumab, ARG201, tocilizumab, ivacftor, dornasealpha, pancrelipase, tobramycin, aztreonam, colistimethate sodium,cefadroxil monohydrate, cefazolin, cephalexin, cefazolin, moxifloxacin,levofloxacin, gemifloxacin, azithromycin, gentamicin, ceftazidime, acombination of trimethoprim and sulfamethoxazole, chloramphenicol, acombination of ivacftor and lumacaftor, ataluren, NT-501-CNTF, a genetransfer agent encoding myosin VIIA (MYO7A), ranibizumab, pegaptanibsodium, NT501, humanized sphingomab, bevacizumab, oseltamivir,zanamivir, rimantadine, amantadine, nafcillin, sulfamethoxazolem,trimethoprim, sulfasalazine, acetyl sulfisoxazole, vancomycin,muromonab-CD3, ASKP-1240, ASP015K, TOL101, pimecrolimus, hydrocortizone,betamethasone, flurandrenolide, triamcinolone, fluocinonide, clobetasol,hydrocortisone, methylprednisolone, prednisolone, a recombinantsynthetic type I interferon, interferon alpha-2a, interferon alpha-2b,hydroxyzine, diphenhydramine, flucloxacillin, dicloxacillin, anderythromycin.

A compound described herein may be administered in combination withother anti-inflammatory agents for any of the indications above,including oral or topical corticosteroids, anti-TNF agents,5-aminosalicyclic acid and mesalamine preparations, hydroxycloroquine,thiopurines, methotrexate, cyclophosphamide, cyclosporine, calcineurininhibitors, mycophenolic acid, mTOR inhibitors, JAK inhibitors, Sykinhibitors, anti-inflammatory biologic agents, including anti-IL6biologics, anti-IL1 agents, anti-IL17 biologics, anti-CD22,anti-integrin agents, anti-IFNa, anti-CD20 or CD4 biologics and othercytokine inhibitors or biologics to T-cell or B-cell receptors orinterleukins.

In the treatment of ALS, a compound described herein may be administeredin combination with riluzole.

In the treatment of Parkinson's disease, a compound described herein maybe administered in combination with levodopa, carbodopa or a combinationthereof, pramipexole, ropinirole, rotigotine, selegiline, rasagiline,entacapone, tolcapone, benztropine, trihexyphenidyl, or amantadine.

In the treatment of Alzheimer's disease, a compound described herein maybe administered in combination with donepezil, galantamine, memantine,rivastigmine, anti-ABeta (amyloid beta) therapies including aducanumab,crenezumab, solanezumab, and gantenerumab, small molecule inhibitors ofBACE1 including verubecestat, AZD3293 (LY3314814), elenbecestat (E2609),LY2886721, PF-05297909, JNJ-54861911, TAK-070, VTP-37948, HPP854,CTS-21166, or anti-tau therapies such as LMTM(leuco-methylthioninium-bis (hydromethanesulfonate)).

In the treatment of rheumatoid arthritis, a compound described hereinmay be administered in combination with ibuprofen, naproxen, prednisone,methotrexate, leflunomide, hydroxychloroquine, sulfasalazine, abatacept,adalimumab, anakinra, certolizumab, etanercept, golimumab, infliximab,rituximab, tocilizumab or tofacitinib.

In the treatment of CVA, a compound described herein may be administeredto in combination with a thrombolytic agent (such as tissue plasminogenactivator (TPA®), Activase®, Lanoteplase®, Reteplase®, Staphylokinase®,Streptokinase®, Tenecteplase®, Urokinase®), an anticoagulant (such asheparin, coumadin, clopidrogel (Plavix®)), and a platelet aggregationinhibitor (such as dipyridamole (Persantine®), ticlopidine HCL(Ticlid®), eptifibatide (Integrillin®), and/or aspirin).

In the treatment of SIRS, a compound described herein may beadministered in combination with a broad-spectrum antibiotic (such asvacomycin) or other anti-MRSA therapy (cefeprime (Maxipime®),piperacillin/tazobactam (Zosyn®), carbapenem (imipenem, meropenem,doripenem), quinolones (ciprofloxacin, levofloxacin, ofloxacin,moxifloxacin, etc.), and low dose steroids such as hydrocortisones.

In the treatment of inflammatory bowel disease (particularly, Crohn'sdisease and/or ulcerative colitis), a compound of any formula describedherein, may be administered in combination with vedolizumab (Entyvio®),alicaforsen, or remestemcel-L (Prochymal®). Specifically, in thetreatment of inflammatory bowel disease (particularly, Crohn's diseaseand/or ulcerative colitis), a compound described herein may beadministered in combination with alicaforsen, or remestemcel-L(Prochymal®). In the treatment of psoriasis, a compound described hereinmay be administered in combination with ixekizumab, tildrakizumab(MK-3222), or secukinumab (AIN457).

Specifically, in the treatment of psoriasis, a compound described hereinmay be administered in combination with ixekizumab, or tildrakizumab(MK-3222). In the treatment of periodonitis, a compound of any formuladescribed herein may be administered in combination with anantimicrobial agent, (such as chlorhexidine (Peridex®, PerioChip®,PerioGard®, etc.)) or an antibiotic (such as doxycycline (Vibrox®,Periostat®, Monodox®, Oracea®, Doryx®, etc.) or minocycline (Dynacin®,Minocin®, Arestin®, Dynacin®, etc.).

In the treatment of asthma, a compound of any formula described hereinmay be administered in combination with an inhaled corticosteroid ((ICS)such as fluticasone proprionate (Flovent®), beclomethasone dipropionate(QVAR®), budesonide (Pulmicort), triamcinolone acetonide (Azmacort®),flunisolide (Aerobid®), mometasone fuorate (Asmanex® Twisthaler®), orCiclesonide (Alvesco®)), a long acting beta agonist ((LABA) such asformoterol fumarate (Foradil®), salmeterol xinafoate (Serevent®)), acombination of an ICS and LABA (such as fluticasone furoate andvilanterol (Breo Ellipta®), formoterol/budesonide inhalation(Symbicort®), beclomethasone dipropionate/formoterol (Inuvair®), andfluticasone propionate/salmeterol (Advair®), a short acting beta agonist((SABA) such as albuterol sulfate (ProAir®, Proventil HFA®, VentolinHFA®, AccuNeb® Inhalation Solution), levalbuterol tartrate (Xopenex®HFA), ipratropium bromide/albuterol (Combivent® Respimat®), ipratropiumbromide (Atrovent® HFA), a leukotriene modifier (such as montelukastsodium (Singulair®), zafirlukast (Accolate®), or zileuton (Zyflo®), andanti-IgE (such as omalizumab (Xolair®)), a methylxanthine bronchodilator(such as theophylline (Accurbron®, Aerolate®, Aquaphyllin®, Asbron®,Bronkodyl®, Duraphyl®, Elixicon®, Elixomin®, Elixophyllin®, Labid®,Lanophyllin®, Quibron-T®, Slo-Bid®, Slo-Phyllin®, Somophyllin®,Sustaire®, Synophylate®, T-Phyll®, Theo-24®, Theo-Dur®, Theobid®,Theochron®, Theoclear®, Theolair®, Theolixir®, Theophyl®, Theovent®,Uni-dur®, Uniphyl®), a mast cell inhibitor (such as cromulyn sodium(Nasalcrom®) and nedocromil sodium (Tilade®)), a long-acting muscarinicantagonist ((LAMA) such as mometasone furoate/formoterol fumaratedihydrate (Dulera®)).

Other agents that may be suitable for use in combination therapy in thetreatment of asthma include a protein tyrosine kinase inhibitor(masitinib), CRTH2/D-prostanoid receptorantagonist (AMG 853),indacaterol (Arcapta® Neohaler®), an epinephrine inhalation aerosol(E004), fluticasone furoate/fluticasone proprionate, vilanterolinhalation/fluticasone furoate powder (Relovair™), fluticasonepropionate/eformoterol fumarate dihydrate (Flutiform®), reslizumab,salbutamol dry-powder inhalation, tiotropium bromide (Spiriva®HandiHaler®), formoterol/budesonide (Symbicort® SMART®), fluticasonefuroate (Veramyst®), Vectura's VR506, lebrikizumab (RG3637), acombination phosphodiesterase (PDE)-3 and (PDE)-4 inhibitor (RPL554).

In the treatment of COPD, a compound of any formula described herein,may be administered in combination with a LABA (such as salmeterolxinafoate (Serevent), umeclidinium/vilanterol (Anuro Ellipta®),umeclidinium (Incruse Ellipta®), arformoterol tartrate (Brovana®),formoterol fumarate inhalation powder (Foradil®), indacterol maleate(Arcapta® Neohaler®), or fluticasone propionate/eformoterol fumaratedehydrate (Flutiform®)), a long-acting inhaled anticholinergic (ormuscarinic antagonist, such as tiotropium bromide (Spiriva®), andaclidinium bromide (Tudorza® Pressair®), a phosphodiesterase (PDE-r)inhibitor (such as roflumilast, Daliresp®), a combination ICS/LABA (suchas fluticasone furoate and vilanterol (Breo Ellipta®), fluticasonepropionate/salmeterol (Advair®), budesonide/formoterol (Symbicort®),mometasone/formoterol (Dulera®), ipratropium bromide/albuterol sulfate(Duoneb®, Atrovent®), albuterol/ipratropium (Combivent Respimat®)), aSABA (such as ipratropium bromide (Atrovent®), and albuterol sulfate(ProAir®, Proventil®)), and an ICS (such as budesonide (Pulmicort®) andfluticasone propionate (Flovent®), beclometasone dipropionate (QVAR®).

Other agents that may be suitable for use in combination therapy in thetreatment of COPD include SCH527123 (a CXCR2 antagonist), glycoprroniumbromide ((NVA237) Seebri® Breezhaler®), glycopyrronium bromide andindacaterol maleate ((QVA149) Ultibro® Breezhaler®), glycopyrrolate andformoterol fumarate (PT003), indacaterol maleate (QVA149), olodaterol(Striverdi® Respimat®), tiotropium (Spiriva®)/olodaterol (Striverdi®Respimat®), and aclidinium/formoterol inhalation.

In the treatment of a mycobacterium infection (tuberculosis), a compoundof any formula described herein may be administered in combination withan antimycobacterial agent (such as isoniazid (INH), ehambutol(Myambutol®), rifampin (Rifadin®), and pyrazinamide (PZA)) abactericidal antibiotic (such as rifabutin (Mycobutin®) or rifapentine(Priftin®)), an aminoglycoside (capreomycin), a fluorquinolone(levofloxacin, moxifloxicin, ofloxacin), thioamide (ehionamide),cyclosporine (Sandimmune®), para-aminosalicyclic acid (Paser®),cycloserine (Seromycin®), kanamycin (Kantrex®), streptomycin, viomycin,capreomycin (Capastat®)), bedaquiline fumarate (Sirturo®), oxazolidinone(Sutezolid®), or delamanid (OPC-67683).

Specifically, in the treatment of a mycobacterium infection(tuberculosis), a compound described herein may be administered incombination with an antimycobacterial agent (such as isoniazid (INH),ehambutol (Myambutol®), rifampin (Rifadin®), and pyrazinamide (PZA)) abactericidal antibiotic (such as rifabutin (Mycobutin®) or rifapentine(Priftin®)), an aminoglycoside (Capreomycin®), a fluorquinolone(levofloxacin, moxifloxicin, ofloxacin), thioamide (ehionamide),cycloserine (Seromycin®), kanamycin (Kantrex®), streptomycin, viomycin,capreomycin (Capastat®)), bedaquiline fumarate (Sirturo®), oxazolidinone(Sutezolid®), or delamanid (OPC-67683).

In the treatment of systemic scleroderma, a compound of any formuladescribed herein may be administered in combination with an oralcorticosteroid (such as prednisolone (Delatsone®, Orapred, Millipred,Omnipred, Econopred, Flo-Pred), an immunosuppressive agent (such asmethotrexate (Rhuematrex®, Trexall®), cyclosporine (Sandimmune®),anti-thymocyte globulin (Atgam®), mycophenolate mofetil (CellCept®),cyclophosphamide (Cytoxan®), FK506 (tacrolimus), thalidomide(Thalomid®), chlorambucil (Leukeran®), azathioprine (Imuran®, Azasan®)),a calcium channel blocker (such as nifedipine (Procardia®, Adalat®) ornicardipine (Cardene®), a topical emollient (nitroglycerin ointment), anACE inhibitor (such as lisinopril (Zestril®, Prinivil®), diltaizem(Cardizem®, Cardizem SR®, Cardizem CD®, Cardia®, Dilacor®, Tiazac®)), aserotonin reuptake inhibitor (such as fluoxetine (Prozac®)), anendothelin-1 receptor inhibitor (such as bosentan (Tracleer®) orepoprostenol (Flolan®, Veletri®, Prostacyclin®)) an anti-fibrotic agent(such as colchicines (Colcrys®), para-aminobenzoic acid (PABA), dimethylsulfoxide (KMSO), and D-penicillamine (Cuprimine®, Depen®), interferonalpha and interferon gamma (INF-g)), a proton-pump Inhibitor (such asomeprazole (Prilosec®), metoclopramide (Reglan®), lansoprazole(Prevacid®), esomeprazole (Nexium®), pantoprazole (Protonix®),rabeprazole (Aciphex®)) or imatinib (Gleevec®) ARG201 (arGentisPharmaceutical), belimumab (Benlysta®), tocilizumab (Actema®).

Specifically, in the treatment of systemic scleroderma, a compound ofany formula described herein may be administered in combination with anoral corticosteroid (such as prednisolone (Delatsone®, Orapred,Millipred, Omnipred, Econopred, Flo-Pred), anti-thymocyte globulin(Atgam®), FK506 (tacrolimus), thalidomide (Thalomid®), chlorambucil(Leukeran®), a calcium channel blocker (such as nifedipine (Procardia®,Adalat®) or nicardipine (Cardene®), a topical emollient (nitroglycerinointment), an ACE inhibitor (such as lisinopril (Zestril®, Prinivil®),diltaizem (Cardizem®, Cardizem SR®, Cardizem CD®, Cardia®, Dilacor®,Tiazac®)), a serotonin reuptake inhibitor (such as fluoxetine(Prozac®)), an endothelin-1 receptor inhibitor (such as bosentan(Tracleer®) or epoprostenol (Flolan, Veletri®, Prostacyclin®)) ananti-fibrotic agent (such as colchicines (Colcrys®), para-aminobenzoicacid (PABA), dimethyl sulfoxide (KMSO), and D-penicillamine (Cuprimine,Depen®), interferon alpha and interferon gamma (INF-g)), a proton-pumpInhibitor (such as omeprazole (Prilosec®), metoclopramide (Reglan®),lansoprazole (Prevacid®), esomeprazole (Nexium®), pantoprazole(Protonix®), rabeprazole (Aciphex®)) or imatinib (Gleevec®) ARG201(arGentis Pharmaceutical), or tocilizumab (Actema®).

In the treatment of cystic fibrosis, a compound as described herein maybe administered in combination with a cystic fibrosis transmembraneconductance regulator (CFTR) potentiator (ivacftor (Kalydeco®)) amucolytic agent (such as dornase alpha (Pulmozyme®)), pancreatic enzymes(such as Pancrelipase (Creon®, Pancreaze®, Ultresa®, Zenpep®)), abronchodilator (such as albuterol (AccuNeb®, ProAir®, Proventil HFA®,VoSpire ER®, Ventolin HFA®)), an antibiotic (including inhaled, oral orparenteral, such as tobramycin solution for inhalation (TOBI®, Bethkis®,TOBI Podhaler®), aztreonam inhalation (Azactam®, Cayston®),colistimethate sodium (Coly-Mycin®), cephalosporins (cefadroxilmonohydrate (Duricef®), cefazolin (Kefzol®), cephalexin (Keflex®),cefazolin (Ancef®, etc.), fluoroquinolones (moxifloxacin, levofloxacin,gemifloxacin, etc), azithromycin (Zithromax®), gentamicin (Garamycin®),piperacillin/tazobacam (Zosyn®), cephalexin (Keflex), ceftazidime(Fortaz, Tazicef), ciprofloxin (Cipro XR, Proquin XR),trimethoprim/sulfamethoxazole (Bactrim DS, Septra DS),chloramphenicol)), or ivacftor (Kalydeco®)/lumacaftor (VX-809), ataluren(Translarna®), or with tiopropium bromide (Spiriva® Handihaler®) as addon to standard therapy.

In the treatment ofretinitis pigmentosa, a compound as described hereinmaybe administered in combination with a ciliary neurotrophic growthfactor (NT-501-CNTF) or gene transfer agent, UshStat.

In the treatment of macular degeneration, a compound of any formuladescribed herein, may be administered in combination with opthalmalicintravitreal injections (afibercept (Eylea®)) or with an anti-vascularendothelial growth factor (VEGF) inhibitor (such as ranibizumab(Lucentis®) or pegaptanib sodium (Macugen®)), a ciliary neurotrophicgrowth factor agent (NT501), iSONEP®, or bevacizumab (Avastin®).

In the treatment of influenza, a compound as described herein may beadministered in combination with a trivalent (IIV3) inactivatedinfluenza vaccine (such as Afluria®, Fluarix®, Flucelvax®, FluLaval®,Fluvirin®, Fluzone®), a quadrivalent (IIV4) inactivated influenzavaccine (such as Fluarix® Quadrivalent, Flulaval® Quadrivalent, Fluzone®Quadrivalent), a trivalent recombinant influenza vaccine (such asFluBlok®), a quadrivalent live attenuated influenza vaccine (such asFluMist® Quadrivalent), an antiviral agent (such as oseltamivir(Tamiflu®), zanamivir (Relenza®), rimantadine (Flumadine®), oramantadine (Symmetrel®)), or Fluad®, Fludase, FluNhance®, Preflucel, orVaxiGrip®

In the treatment of a staphylococcus infection, a compound of anyformula described herein may be administered in combination with anantibiotic (such as a-Lactam cephalosporin (Duricef®, Kefzol®, Ancef®,Biocef®, etc), nafcillin (Unipen®), a sulfonamide (sulfamethoxazole andtrimethoprim (Bacrim®, Septra®,) sulfasalazine (Azulfidine®), acetylsulfisoxazole (Gantrisin®), etc), or vancomycin (Vancocin®)).

In the treatment of transplant rejection, a compound of any formuladescribed herein may be administered in combination with a high-dosecorticosteroid (such as prednisone (Deltasone®), methylprednisolone(SoluMedrol®) etc.) a calcineurin inhibitor (such as cyclosporine(Sandimmune®, Neoral®, Gengraf®), tacrolimus (Prograf®, Astragraf XL®)),an mTor inhibitor (such as sirolimus (Rapamune) or everolimus(Afinitor®)), an anti-proliferative agent (such as azathioprine(Imuran®, Azasan®), mycophenolate mofetil (CellCept®), or mycophenolatesodium (Myfortic®)), a monoclonal antibody (such as muromonab-CD3(Orthoclone OKT3®)), an interleukine-2 receptor antagonist((Basiliximab, Simulect®), daclizumab (Zenapax®), or rituximab(Rituxan®)), a polyclonal anti-T-cell antibody (such as anti-thymocytegamma globulin-equine (Atgam®), or antithymocyte globulin-rabbit(Thymoglobulin®)) an anti-CD40 antagonist (ASKP-1240), a JAK inhibitor(ASP015K), or an anti-TCR murine mAb (TOL101).

Specifically, in the treatment of transplant rejection, a compound ofany formula described herein may be administered in combination with amonoclonal antibody (such as muromonab-CD3 (Orthoclone OKT3®)), apolyclonal anti-T-cell antibody (such as anti-thymocyte gammaglobulin-equine (Atgam®), or antithymocyte globulin-rabbit(Thymoglobulin®)) an anti-CD40 antagonist (ASKP-1240), a JAK inhibitor(ASP015K), or an anti-TCR murine mAb (TOL101).

In the treatment of atopic dermatitis, a compound of any formuladescribed herein may be administered in combination with a topicalimmunomodulator or calcineurin inhibitor (such as pimecrolimus (Elidel®)or tacrolimus ointment (Protopic®)), a topical corticosteroid (such ashydrocortizone (Synacort®, Westcort®), betamethasone (Diprolene®),flurandrenolide (Cordan®), fluticasone (Cutivate®), triamcinolone(Kenalog®), fluocinonide (Lidex®), and clobetasol (Temovate®)), an oralcorticosteroid (such as hydrocortisone (Cortef®), methylprednisolone(Medrol®), or prednisolone (Pediapred®, Prelone®), an immunosuppressant(such as cyclosporine (Neoral®) or interferon gamma (Alferon N®,Infergen®, Intron A, Roferon-A®)), an antihistamine (for itching such asAtarax®, Vistaril®, Benadryl®), an antibiotic (such as penicillinderivatives flucloxacillin (Floxapen®) or dicloxacillin (Dynapen®),erythromycin (Eryc®, T-Stat®, Erythra-Derm®, etc.)), anon-steroidalimmunosuppressive agent (such as azathioprine (Imuran®, Azasan®),methotrexate (Rhuematrex®, Trexall®), cyclosporine (Sandimmune®), ormycophenolate mofetil (CellCept®)).

Specifically, in the treatment of atopic dermatitis, a compound of anyformula described herein may be administered in combination with atopical immunomodulator or calcineurin inhibitor (such as pimecrolimus(Elidel®) or tacrolimus ointment (Protopic®)), a topical corticosteroid(such as hydrocortizone (Synacort®, Westcort®), betamethasone(Diprolene®), flurandrenolide (Cordan®), fluticasone (Cutivate®),triamcinolone (Kenalog®), fluocinonide (Lidex®), and clobetasol(Temovate®)), an oral corticosteroid (such as hydrocortisone (Cortef®),methylprednisolone (Medrol®), or prednisolone (Pediapred®, Prelone®), aninterferon gamma (Alferon N®, Infergen®, Intron A, Roferon-A®)), anantihistamine (for itching such as Atarax®, Vistaril®, Benadryl®), or anantibiotic (such as penicillin derivatives flucloxacillin (Floxapen®) ordicloxacillin (Dynapen®), erythromycin (Eryc®, T-Stat®, Erythra-Derm®,etc.)).

In the treatment of burns, e.g. a burn injury or burn shock, a compoundof any formula described herein may be administered alone, or incombination with an antimicrobial agent, typically a topical antibiotic(mafenide acetate cream, silver sulfadiazine cream) and/or a analgesic(opioid analgesics, e.g., morphine, oxycodone). Other therapeutic agentsthat may be useful for the treatment of burns include retinoids andpirfenidone.

In certain embodiments, the at least one other therapeutically activeagent is selected from a thrombolytic agent, a tissue plasminogenactivator, an anticoagulant, and a platelet aggregation inhibitor. Incertain embodiments, the at least one other therapeutically active agentis selected from heparin, coumadin, clopidrogel, dipyridamole,ticlopidine HCL, eptifibatide, and aspirin. In certain embodiments, thekinase-mediated disease or disorder treated with these agents is acerebrovascular accident.

In certain embodiments, the at least one other therapeutically activeagent is selected from broad-spectrum antibiotic, anti-MRSA therapy anda low dose steroid. In certain embodiments, the at least one othertherapeutically active agent is selected from vacomycin, cefeprime, acombination of piperacillin and tazobactam, imipenem, meropenem,doripenem, ciprofloxacin, levofloxacin, ofloxacin, moxifloxacin, andhydrocortisone. In certain embodiments, the disease or disorder treatedwith these agents is systemic inflammatory response syndrome.

In certain embodiments, the at least one other therapeutically activeagent is alicaforsen or remestemcel-L. In certain embodiments, thedisease or disorder treated with these agents is Crohn's disease orulcerative colitis.

In certain embodiments, the at least one other therapeutically activeagent is ixekizumab, or tildrakizumab. In certain embodiments, thekinase-mediated disease or disorder treated with these agents ispsoriasis.

In certain embodiments, the at least one other therapeutically activeagent is an antimicrobial agent or an antibiotic. In certainembodiments, the at least one other therapeutically active agent isselected from chlorhexidine, doxycycline and minocycline. In certainembodiments, the disease or disorder treated with these agents isperiodonitis.

In certain embodiments, the at least one other therapeutically activeagent is selected from an inhaled corticosteroid, a long acting betaagonist, a combination of an inhaled corticosteroid and a long actingbeta agonist, a short acting beta agonist, a leukotriene modifier, ananti-IgE, a methylxanthine bronchodilator, a mast cell inhibitor, and along-acting muscarinic antagonist. In certain embodiments, the at leastone other therapeutically active agent is selected from fluticasoneproprionate, beclomethasone dipropionate, budesonide, trimcinoloneacetonide, flunisolide, mometasone fuorate, or ciclesonide, formoterolfumarate, salmeterol xinafoate, a combination of fluticasone furoate andvilanterol, a combination of formoterol and budesonide inhalation, acombination of beclomethasone dipropionate and formoterol, a combinationof fluticasone propionate and salmeterol, albuterol sulfate,levalbuterol tartrate, a combination of ipratropium bromide andalbuterol, ipratropium bromide, montelukast sodium, zafirlukast,zileuton, omalizumab theophylline, cromulyn sodium, nedocromil sodium,and a combination of mometasone furoate and formoterol fumaratedihydrate. In certain embodiments, the at least one othertherapeutically active agent is selected from protein tyrosine kinaseinhibitor, a CRTH2/D-prostanoid receptor antagonist, an epinephrineinhalation aerosol, and a combination of a phosphodiesterase-3 inhibitorand a phosphodiesterase-4 inhibitor. In certain embodiments, the atleast one other therapeutically active agent is selected from masitinib,AMG 853, indacaterol, E004, a combination of fluticasone furoate andfluticasone proprionate, a combination of vinanterol fluticasonefuroate, a combination of fluticasone propionate and eformoterolfumarate dihydrate, reslizumab, salbutamol, tiotropium bromide, acombination of formoterol and budesonide, fluticasone furoate, VR506,lebrikizumab, and RPL554. In certain embodiments, the kinase-mediateddisease or disorder treated with these agents is asthma.

In certain embodiments, the at least one other therapeutically activeagent is selected from a long acting beta agonist, a long-acting inhaledanticholinergic or muscarinic antagonist, a phosphodiesterase inhibitor,a combination an inhaled corticosteroid long acting beta agonist, ashort acting beta agonist, and an inhaled corticosteroid. In certainembodiments, the at least one other therapeutically active agent isselected from salmeterol xinafoate, a combination of umeclidinium andvilanterol, umeclidinium, arformoterol tartrate, formoterol fumarate,indacterol maleate, a combination of fluticasone propionate andeformoterol fumarate dihydrate, tiotropium bromide, aclidinium bromide,roflumilast, a combination of fluticasone furoate and vilanterol, acombination of fluticasone propionate and salmeterol, a combination ofbudesonide and formoterol, a combination of mometasone and formoterol, acombination of ipratropium bromide and albuterol sulfate, a combinationof albuterol and ipratropium, ipratropium bromide, albuterol sulfate,budesonide, fluticasone propionate, and beclometasone dipropionate. Incertain embodiments, the at least one other therapeutically active agentis selected from SCH527123, glycoprronium bromide, a combination ofglycopyrronium bromide and indacaterol maleate, a combination ofglycopyrrolate and formoterol fumarate, indacaterol maleate, olodaterol,tiotropium, olodaterol, and a combination of aclidinium and formoterol.In certain embodiments, the disease or disorder treated with theseagents is COPD.

In certain embodiments, the at least one other therapeutically activeagent is an antimycobacterial agent or a bactericidal antibiotic. Incertain embodiments, the at least one other therapeutically active agentis selected from isoniazid, ehambutol, rifampin, pyrazinamide,rifabutin, rifapentine, capreomycin, levofloxacin, moxifloxicin,ofloxacin, ehionamide, cycloserine, kanamycin, streptomycin, viomycin,bedaquiline fumarate, PNU-100480, and delamanid. In certain embodiments,the kinase-mediated disease or disorder treated with these agents is amycobacterium infection.

In certain embodiments, the at least one other therapeutically activeagent is selected from an oral corticosteroid, anti-thymocyte globulin,thalidomide, chlorambucil, a calcium channel blocker, a topicalemollient, an ACE inhibitor, a serotonin reuptake inhibitor, anendothelin-1 receptor inhibitor, an anti-fibrotic agent, a proton-pumpinhibitor or imatinib, ARG201, and tocilizumab. In certain embodiments,the at least one active agent is selected from prednisolone,anti-thymocyte globulin, FK506 (tacrolimus), thalidomide, chlorambucil,nifedipine, nicardipine, nitroglycerin ointment, lisinopril, diltaizem,fluoxetine, bosentan, epoprostenol, colchicines, para-aminobenzoic acid,dimethyl sulfoxide, D-penicillamine, interferon alpha, interferon gamma(INF-g)), omeprazole, metoclopramide, lansoprazole, esomeprazole,pantoprazole, rabeprazole, imatinib, ARG201, and tocilizumab. In certainembodiments, the disease or disorder treated with these agents issystemic scleroderma.

In certain embodiments, the at least one other therapeutically activeagent is selected from a cystic fibrosis transmembrane conductanceregulator potentiator, amucolytic agent, pancreatic enzymes, abronchodilator, an antibiotic, or ivacftor/lumacaftor, ataluren, andtiopropium bromide. In certain embodiments, the at least one othertherapeutically active agent is selected from ivacftor, dornase alpha,pancrelipase, albuterol, tobramycin, aztreonam, colistimethate sodium,cefadroxil monohydrate, cefazolin, cephalexin, cefazolin, moxifloxacin,levofloxacin, gemifloxacin, azithromycin, gentamicin,piperacillin/tazobacam, ceftazidime, ciprofloxin,trimethoprim/sulfamethoxazole, chloramphenicol, or ivacftor/lumacaftor,ataluren, and tiopropium bromide. In certain embodiments, the disease ordisorder treated with these agents is cystic fibrosis.

In certain embodiments, the at least one other therapeutically activeagent is a ciliary neurotrophic growth factor or a gene transfer agent.In certain embodiments, the at least one other therapeutically activeagent is NT-501-CNTF or a gene transfer agent encoding myosin VIIA(MY07A). In certain embodiments, the disease or disorder treated withthese agents is retinitis pigmentosa.

In certain embodiments, the at least one other therapeutically activeagent is selected from opthalmalic intravitreal injections, ananti-vascular endothelial growth factor inhibitor, and a ciliaryneurotrophic growth factor agent. In certain embodiments, the at leastone other therapeutically active agent is selected from afibercept,ranibizumab, pegaptanib sodium, NT501, humanized sphingomab, andbevacizumab. In certain embodiments, the disease or disorder treatedwith these agents is macular degeneration.

In certain embodiments, the at least one other therapeutically activeagent is selected from a trivalent (IIV3) inactivated influenza vaccine,a quadrivalent (IIV4) inactivated influenza vaccine, a trivalentrecombinant influenza vaccine, a quadrivalent live attenuated influenzavaccine, an antiviral agent, or inactivated influenza vaccine. Incertain embodiments, the at least one other therapeutically active agentis selected from oseltamivir, zanamivir, rimantadine, or amantadine. Incertain embodiments, the kinase-mediated disease or disorder treatedwith these agents is influenza.

In certain embodiments, the at least one other therapeutically activeagent is selected from a beta-Lactam, nafcillin, sulfamethoxazolem,trimethoprim, sulfasalazine, acetyl sulfisoxazole, and vancomycin. Incertain embodiments, disease or disorder treated with these agents is astaphylococcus infection.

In certain embodiments, the at least one other therapeutically activeagent is selected from a monoclonal antibody, a polyclonal anti-T-cellantibody, an anti-thymocyte gamma globulin-equine antibody, anantithymocyte globulin-rabbit antibody, an anti-CD40 antagonist, a JAKinhibitor, and an anti-TCR murine mAb.

In certain embodiments, the at least one other therapeutically activeagent is selected from muromonab-CD3, ASKP-1240, ASP015K, and TOL101. Incertain embodiments, the disease or disorder treated with these agentsis transplant rejection.

In certain embodiments, the at least one other therapeutically activeagent is selected from a topical immunomodulator or calcineurininhibitor, a topical corticosteroid, an oral corticosteroid, aninterferon gamma, an antihistamine, or an antibiotic. In certainembodiments, the at least one other therapeutically active agent isselected from pimecrolimus, tacrolimus, hydrocortizone, betamethasone,flurandrenolide, fluticasone, triamcinolone, fluocinonide, clobetasol,hydrocortisone, methylprednisolone, prednisolone, an interferon alphaprotein, a recombinant synthetic type I interferon, interferon alpha-2a,interferon alpha-2b, hydroxyzine, diphenhydramine, flucloxacillin,dicloxacillin, and erythromycin. In certain embodiments, the disease ordisorder treated with these agents is atopic dermatitis.

8. Dosing

The specific dose level of a compound of the present application for anyparticular subject will depend upon a variety of factors including theactivity of the specific compound employed, the age, body weight,general health, sex, diet, time of administration, route ofadministration, and rate of excretion, drug combination and the severityof the particular disease in the subject undergoing therapy. Forexample, a dosage may be expressed as a number of milligrams of acompound described herein per kilogram of the subject's body weight(mg/kg). Dosages of between about 0.1 and 150 mg/kg may be appropriate.In certain embodiments, about 0.1 and 100 mg/kg may be appropriate. Inother embodiments a dosage of between 0.5 and 60 mg/kg may beappropriate. Normalizing according to the subject's body weight isparticularly useful when adjusting dosages between subjects of widelydisparate size, such as occurs when using the drug in both children andadult humans or when converting an effective dosage in a non-humansubject such as dog to a dosage suitable for a human subject.

The daily dosage may also be described as a total amount of a compounddisclosed herein administered per dose or per day. Daily dosage of acompound disclosed herein may be between about 1 mg and 4,000 mg,between about 2,000 to 4,000 mg/day, between about 1 to 2,000 mg/day,between about 1 to 1,000 mg/day, between about 10 to 500 mg/day, betweenabout 20 to 500 mg/day, between about 50 to 300 mg/day, between about 75to 200 mg/day, or between about 15 to 150 mg/day.

When administered orally, the total daily dosage for a human subject maybe between 1 mg and 1,000 mg, between about 1,000-2,000 mg/day, betweenabout 10-500 mg/day, between about 50-300 mg/day, between about 75-200mg/day, or between about 100-150 mg/day.

The compounds of the present application or the compositions thereof maybe administered once, twice, three, or four times daily, using anysuitable mode described above. Also, administration or treatment withthe compounds may be continued for a number of days; for example,commonly treatment would continue for at least 7 days, 14 days, or 28days, for one cycle of treatment. Treatment cycles are well known incancer chemotherapy, and are frequently alternated with resting periodsof about 1 to 28 days, commonly about 7 days or about 14 days, betweencycles. The treatment cycles, in other embodiments, may also becontinuous.

In certain embodiments, the method comprises administering to thesubject an initial daily dose of about 1 to 800 mg of a compounddescribed herein and increasing the dose by increments until clinicalefficacy is achieved. Increments of about 5, 10, 25, 50, or 100 mg canbe used to increase the dose. The dosage can be increased daily, everyother day, twice per week, or once per week.

9. Synthesis of the Compounds

The compounds may be prepared using the methods disclosed herein androutine modifications thereof, which will be apparent given thedisclosure herein and methods well known in the art. Conventional andwell-known synthetic methods may be used in addition to the teachingsherein. The synthesis of typical compounds described herein may beaccomplished as described in the following examples. If available,reagents may be purchased commercially, e.g., from Sigma Aldrich orother chemical suppliers.

The compounds of the disclosure may be prepared using methods disclosedherein and routine modifications thereof which will be apparent giventhe disclosure herein and methods well known in the art. Conventionaland well-known synthetic methods may be used in addition to theteachings herein. The synthesis of typical compounds described herein,e.g. compounds having structures described by one or more formulas orcompounds disclosed herein, may be accomplished as described in thefollowing examples. If available, reagents may be purchasedcommercially, e.g. from Sigma Aldrich or other chemical suppliers.

The compounds of this disclosure can be prepared from readily availablestarting materials using, for example, the following general methods andprocedures. It will be appreciated that where typical or preferredprocess conditions (i.e., reaction temperatures, times, mole ratios ofreactants, solvents, pressures, etc.) are given, other processconditions can also be used unless otherwise stated. Optimum reactionconditions may vary with the particular reactants or solvent used, butsuch conditions can be determined by one skilled in the art by routineoptimization procedures.

Additionally, as will be apparent to those skilled in the art,conventional protecting groups may be necessary to prevent certainfunctional groups from undergoing undesired reactions. Suitableprotecting groups for various functional groups as well as suitableconditions for protecting and deprotecting particular functional groupsare well known in the art. For example, numerous protecting groups aredescribed in Wuts, P. G. M., Greene, T. W., & Greene, T. W. (2006).Greene's protective groups in organic synthesis. Hoboken, N.J.,Wiley-Interscience, and references cited therein.

Furthermore, the compounds of this disclosure may contain one or morechiral centers. Accordingly, if desired, such compounds can be preparedor isolated as pure stereoisomers, i.e., as individual enantiomers ordiastereomers or as stereoisomer-enriched mixtures. All suchstereoisomers (and enriched mixtures) are included within the scope ofthis disclosure, unless otherwise indicated. Pure stereoisomers (orenriched mixtures) may be prepared using, for example, optically activestarting materials or stereoselective reagents well-known in the art.Alternatively, racemic mixtures of such compounds can be separatedusing, for example, chiral column chromatography, chiral resolvingagents, and the like.

The starting materials for the following reactions are generally knowncompounds or can be prepared by known procedures or obviousmodifications thereof. For example, many of the starting materials areavailable from commercial suppliers such as Aldrich Chemical Co.(Milwaukee, Wis., USA), Bachem (Torrance, Calif., USA), Emka-Chemce orSigma (St. Louis, Mo., USA). Others may be prepared by procedures orobvious modifications thereof, described in standard reference textssuch as Fieser and Fieser's Reagents for Organic Synthesis, Volumes 1-15(John Wiley, and Sons, 1991), Rodd's Chemistry of Carbon Compounds,Volumes 1-5, and Supplementals (Elsevier Science Publishers, 1989)organic Reactions, Volumes 1-40 (John Wiley, and Sons, 1991), March'sAdvanced Organic Chemistry, (John Wiley, and Sons, 5 Edition, 2001), andLarock's Comprehensive Organic Transformations (VCH Publishers Inc.,1989).

The terms “solvent,” “inert organic solvent” or “inert solvent” refer toa solvent inert under the conditions of the reaction being described inconjunction therewith (including, for example, benzene, toluene,acetonitrile, tetrahydrofuran (“THF”), dimethylformamide (“DMF”),chloroform, methylene chloride (or dichloromethane), diethyl ether,methanol, pyridine and the like). Unless specified to the contrary, thesolvents used in the reactions of the present disclosure are inertorganic solvents, and the reactions are carried out under an inert gas,preferably nitrogen.

The term “q.s.” means adding a quantity sufficient to achieve a statedfunction, e.g., to bring a solution to the desired volume (i.e., 100%).

Scheme 1 shows the synthesis of compounds of Formula I, wherein LG is aleaving group and X¹, X², Y¹, Y², A, L, R², R³, R⁴, and R⁹, are asdefined herein.

As depicted in Scheme 1, the compounds of Formula I may be prepared bycontacting a suitably substituted 1-a with compound 1-b, under standardamide bond forming reaction conditions. As is typical in peptidecoupling reactions, an activating agent may be used to facilitate thereaction. Suitable coupling agents (or activating agents) are known inthe art and include for example, carbodiimides (e.g.,N,N′-dicyclohexylcarbodiimide (DCC), N,N′-dicyclopentylcarbodiimide,N,N′-diisopropylcarbodiimide (DIC),1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC),N-t-butyl-N-methylcarbodiimide (BMC), N-t-butyl-N-ethylcarbodiimide(BEC), 1,3-bis(2,2-dimethyl-1,3-dioxolan-4-ylmethyl)carbodiimide (BDDC),etc.), anhydrides (e.g., symmetric, mixed, or cyclic anhydrides),activated esters (e.g., phenyl activated ester derivatives, p-hydroxamicactivated ester, hexafluoroacetone (HFA), etc.), acylazoles(acylimidazoles using CDI, acylbenzotriazoles, etc.), acyl azides, acidhalides, phosphonium salts (HOBt, PyBOP, HOAt, etc.), aminium/uroniumsalts (e.g., tetramethyl aminium salts, bispyrrolidino aminium salts,bispiperidino aminium salts, imidazolium uronium salts, pyrimidiniumuronium salts, uronium salts derived fromN,N,N′-trimethyl-N′-phenylurea, morpholino-based aminium/uroniumcoupling reagents, antimoniate uronium salts, etc.), organophosphorusreagents (e.g., phosphinic and phosphoric acid derivatives),organosulfur reagents (e.g., sulfonic acid derivatives), triazinecoupling reagents (e.g., 2-chloro-4,6-dimethoxy-1,3,5-triazine,4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4 methylmorpholinium chloride,4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4 methylmorpholiniumtetrafluoroborate, etc.), pyridinium coupling reagents (e.g.,Mukaiyama's reagent, pyridinium tetrafluoroborate coupling reagents,etc.), polymer-supported reagents (e.g., polymer-bound carbodiimide,polymer-bound TBTU, polymer-bound 2,4,6-trichloro-1,3,5-triazine,polymer-bound HOBt, polymer-bound HOSu, polymer-bound IIDQ,polymer-bound EEDQ, etc.), and the like (see, e.g., El-Faham, et al.Chem. Rev., 2011, 111(11): 6557-6602; Han, et al. Tetrahedron, 2004,60:2447-2467). Compounds of formula 1-a and 1-b for use in Scheme 1 maybe obtained as described in the schemes and Examples provided herein orfrom conventional synthetic methods known in the art using appropriatestarting materials.

Scheme 2 shows an exemplary synthesis for compounds which contain a6,7-fused ring and where Y¹ is O. In Scheme 2, PG is a protecting group(e.g., BOC) and X⁶, X⁷, X⁸, X⁹, Y², q, R¹, R³, R⁴, and R¹⁰ are asdefined herein.

In Scheme 2, appropriately substituted 2-a can be cyclized understandard amide bond forming reaction conditions (e.g., as describedabove). Compounds of formula 2-a may be obtained from commercialsources, or prepared as described in the Examples provided herein orfrom conventional synthetic methods known in the art using appropriatestarting materials. Further, the desired functional groups at Y², R¹,R³, R⁴ and R¹⁰ may be installed prior to, or after, cyclization byemploying conventional synthetic methods known in the art (e.g.,halogenation, reduction, oxidation, olefination, alkylation, etc.).

Scheme 3 shows an exemplary synthesis for compounds which contain a5,7-fused ring and where Y¹ is O. In Scheme 3, Z is halo and X¹, X², X³,X⁴, X⁵, Y², q, R¹, R³, R⁴, and R¹⁰ are as defined herein.

In Scheme 3, appropriately substituted 3-a can be contacted withhydroxylamine hydrochloride under reaction conditions sufficient toprovide 3-b. Ring expansion of 3-b to provide lactam 3-c can beperformed by contacting oxime 3-b with phosphorus pentoxide.Alternatively, lactam 3-c can be provided by contacting 3-a with sodiumazide in the presence of sulfuric acid. α-Halogenation of 3-c using asuitable reagent (e.g., NBS, iodotrimethylsilane, etc.) and optionalN-alkylation of the azapanone nitrogen with a compound of formula R¹-LG,where LG is a suitable leaving group (e.g., halo) provides 3-d.Contacting 3-d with sodium azide yields 3-e. Reduction of the azide in3-e (e.g., hydrogenation, triphenylphosphine, etc.) provides 3-f.Compounds of formula 3-a may be obtained from commercial sources, orprepared as described in the Examples provided herein or fromconventional synthetic methods known in the art using appropriatestarting materials. Further, alternative functional groups may beinstalled at any point prior to, during, or after, the steps shown inScheme 3 by employing conventional synthetic methods known in the art(e.g., halogenation, reduction, oxidation, olefination, alkylation,etc.).

Also provided herein is a process for preparing a compound of FormulaII:

or a salt, tautomer, stereoisomer or mixture of stereoisomers thereof,comprising contacting a compound of Formula XVI or a salt, tautomer,stereoisomer or mixture of stereoisomers thereof:

and contacting a compound of Formula XVI or a salt, tautomer,stereoisomer or mixture of stereoisomers thereof, with a compound ofFormula XVII:

under reaction conditions sufficient to provide the compound of FormulaII or a salt, tautomer, stereoisomer or mixture of stereoisomersthereof, wherein

Y² is —O—, —S—, or —NR⁵—;

R⁵ is H or optionally substituted C₁-C₆ alkyl; and

L, ring A, q, R¹, R³, R⁴, R⁹, R¹⁰, X⁶, X⁷, X⁸ and X⁹ are as definedherein.

In certain embodiments, provided is a process for preparing a compoundof Formula II:

or a salt, tautomer, stereoisomer or mixture of stereoisomers thereof,comprising:

(a) contacting a compound of Formula X:

or a salt, tautomer, stereoisomer or mixture of stereoisomers thereof,with a compound of Formula XI:

under reaction conditions sufficient to provide the compound of FormulaXII or a salt, tautomer, stereoisomer or mixture of stereoisomersthereof:

(b) contacting a compound of Formula XII or a salt, tautomer,stereoisomer or mixture of stereoisomers thereof, under reactionconditions sufficient to provide the compound of Formula (XIII) or asalt, tautomer, stereoisomer or mixture of stereoisomers thereof:

(c) contacting a compound of Formula XIII or a salt, tautomer,stereoisomer or mixture of stereoisomers thereof, under reactionconditions sufficient to provide the compound of Formula XIV or a salt,tautomer, stereoisomer or mixture of stereoisomers thereof:

(d) optionally contacting a compound of Formula XIV or a salt, tautomer,stereoisomer or mixture of stereoisomers thereof, with an alkylatingagent, under reaction conditions sufficient to provide the compound ofFormula XV or a salt, tautomer, stereoisomer or mixture of stereoisomersthereof:

(e) deprotecting the compound of Formula XV or a salt, tautomer,stereoisomer or mixture of stereoisomers thereof, under reactionconditions sufficient to provide the compound of Formula XVI or a salt,tautomer, stereoisomer or mixture of stereoisomers thereof:

and contacting a compound of Formula XVI or a salt, tautomer,stereoisomer or mixture of stereoisomers thereof, with a compound ofFormula XVII:

under reaction conditions sufficient to provide the compound of FormulaII or a salt, tautomer, stereoisomer or mixture of stereoisomersthereof, wherein

P is a protecting group;

Y² is —O—, —S—, or —NR⁵—;

R⁵ is H or optionally substituted C₁-C₆ alkyl; and

L, ring A, q, R¹, R³, R⁴, R⁹, R¹⁰, X⁶, X⁷, X⁸ and X⁹ are as definedherein.

In certain embodiments of the processes described above, at least one ofX⁷ or X⁹ is N. In certain embodiments of the processes described above,X⁷ is N and X⁶, X⁸ and X⁹ are CH. In certain embodiments of theprocesses described above, X⁹ is N and X⁶, X⁷ and X⁸ are CH. In certainembodiments of the processes described above, R¹ is methyl. In certainembodiments of the processes described above, Y² is —O—.

In certain embodiments of the processes described above, P istert-butoxycarbonyl. In certain embodiments of the processes describedabove, the reaction conditions of step (b) comprise hydrogen gas. Incertain embodiments of the processes described above, the reactionconditions of step (c) comprise a peptide coupling agent. In certainembodiments of the processes described above, the alkylating agent ofstep (d) is methyliodide.

It will also be appreciated that in each of the above schemes, theaddition of any substituent may result in the production of a number ofisomeric products (including, but not limited to, enantiomers or one ormore diastereomers) any or all of which may be isolated and purifiedusing conventional techniques. When enantiomerically pure or enrichedcompounds are desired, chiral chromatography and/or enantiomericallypure or enriched starting materials may be employed as conventionallyused in the art or as described in the Examples.

EXAMPLES

The following examples are included to demonstrate specific embodimentsof the disclosure. It should be appreciated by those of skill in the artthat the techniques disclosed in the examples which follow representtechniques to function well in the practice of the disclosure, and thuscan be considered to constitute specific modes for its practice.However, those of skill in the art should, in light of the presentdisclosure, appreciate that many changes can be made in the specificembodiments which are disclosed and still obtain a like or similarresult without departing from the spirit and scope of the disclosure.

General Procedures

Liquid Chromatography-Mass Spectrometry Method A:

Total ion current (TIC) and DAD UV chromatographic traces together withMS and UV spectra associated with the peaks were taken on a UPLC/MSAcquity™ system equipped with PDA detector and coupled to a Waterssingle quadrupole mass spectrometer operating in alternated positive andnegative electrospray ionization mode. [LC/MS-ES (+/−): analysesperformed using an Acquity UPLC™ CSH, C18 column (50×2.1 mm, 1.7 μmparticle size), column temperature 40° C., mobile phase: A-water+0.1%HCOOH/B-CH₃CN+0.1% HCOOH, flow rate: 1.0 mL/min, run time=2.0 min,gradient: t=0 min 3% B, t=1.5 min 99.9% B, t=1.9 min 99.9% B, t=2.0 min3% B, stop time 2.0 min. Positive ES 100-1000, Negative ES 100-1000, UVdetection DAD 210-350 nm.

Liquid Chromatography-Mass Spectrometry Method B:

Total ion current (TIC) and DAD UV chromatographic traces together withMS and UV spectra associated with the peaks were taken on a UPLC/MSAcquity™ system equipped with PDA detector and coupled to a Waterssingle quadrupole mass spectrometer operating in alternated positive andnegative electrospray ionization mode. [LC/MS-ES (+/−): analysesperformed using an Acquity UPLC™ BEH, C18 column (50×2.1 mm, 1.7 μmparticle size), column temperature 40° C., mobile phase: A—0.1% v/vaqueous ammonia solution pH 10/B-CH₃CN, flow rate: 1.0 mL/min, runtime=2.0 min, gradient: t=0 min 3% B, t=1.5 min 99.9% B, t=1.9 min 99.9%B, t=2.0 min 3% B, stop time 2.0 min. Positive ES 100-1000, Negative ES100-1000, UV detection DAD 210-350 nm.

Liquid Chromatography-Mass Spectrometry Method C:

LCMS analyses were performed on a SHIMADZU LCMS consisting of an UFLC20-AD and LCMS 2020 MS detector. The Diode Array Detector was scannedfrom 190-400 nm. The mass spectrometer was equipped with an electrosprayion source (ESI) operated in a positive or negative mode. The massspectrometer was scanned between m/z 90-900 with a scan time from 0.5 to1.0 s. The column used was a Shim-pack XR-ODS, 2.2 μm, 3.0×50 mm. Alinear gradient was applied, starting at 95% A (A: 0.05% TFA in water)and ending at 100% B (B: 0.05% TFA in MeCN) over 2.2 min with a totalrun time of 2.6 min. The column temperature was at 40° C. with a flowrate of 1.0 mL/min.

Liquid Chromatography-Mass Spectrometry Method D:

LCMS analyses were performed on a SHIMADZU LCMS consisting of an UFLC20-AD and LCMS 2020 MS detector. The Diode Array Detector was scannedfrom 190-400 nm. The mass spectrometer was equipped with an electrosprayion source (ESI) operated in a positive or negative mode. The massspectrometer was scanned between m/z 90-900 with a scan time from 0.5 to1.0 s. The column used was a Shim-pack XR-ODS, 2.2 μm, 3.0×50 mm. Alinear gradient was applied, starting at 95% A (A: 0.05% TFA in water)and ending at 100% B (B: 0.05% TFA in MeCN) over 3.2 min with a totalrun time of 3.6 min. The column temperature was at 40° C. with a flowrate of 1.0 mL/min.

Liquid Chromatography-Mass Spectrometry Method E:

LCMS analyses were performed on a SHIMADZU LCMS consisting of an UFLC20-AD and LCMS 2020 MS detector. The Diode Array Detector was scannedfrom 190-400 nm. The mass spectrometer was equipped with an electrosprayion source (ESI) operated in a positive or negative mode. The massspectrometer was scanned between m/z 90-900 with a scan time from 0.5 to1.0 s. The column used was an Ascentis Express C18, 2.7 μm, 3.0×50 mm. Alinear gradient was applied, starting at 95% A (A: 0.05% TFA in water)and ending at 100% B (B: 0.05% TFA in MeCN) over 1.8 min with a totalrun time of 2.0 min. The column temperature was at 45° C. with a flowrate of 1.5 mL/min.

Liquid Chromatography-Mass Spectrometry Method F:

LCMS analyses were performed on a SHIMADZU LCMS consisting of an UFLC20-AD and LCMS 2020 MS detector. The Diode Array Detector was scannedfrom 190-400 nm. The mass spectrometer was equipped with an electrosprayion source (ESI) operated in a positive or negative mode. The massspectrometer was scanned between m/z 90-900 with a scan time from 0.5 to1.0 s. The column used was an Ascentis Express C18, 2.7 μm, 3.0×50 mm. Alinear gradient was applied, starting at 95% A (A: 0.05% TFA in water)and ending at 100% B (B: 0.05% TFA in MeCN) over 2.8 min with a totalrun time of 3.0 min. The column temperature was at 45° C. with a flowrate of 1.5 mL/min.

Liquid Chromatography-Mass Spectrometry Method G:

LCMS analyses were performed on a SHIMADZU LCMS consisting of an UFLC20-AD and LCMS 2020 MS detector. The Diode Array Detector was scannedfrom 190-400 nm. The mass spectrometer was equipped with an electrosprayion source (ESI) operated in a positive or negative mode. The massspectrometer was scanned between m/z 90-900 with a scan time from 0.5 to1.0 s. The column used was a Kinetex EVO, 2.6 μm, 3.0×50 mm. A lineargradient was applied, starting at 90% A (A: 0.05% NH₄HCO₃ in water) andending at 95% B (B: MeCN) over 1.7 min with a total run time of 2.0 min.The column temperature was at 40° C. with a flow rate of 1.3 mL/min.

Liquid Chromatography-Mass Spectrometry Method H:

LCMS analyses were performed on a SHIMADZU LCMS consisting of an UFLC20-AD and LCMS 2020 MS detector. The Diode Array Detector was scannedfrom 190-400 nm. The mass spectrometer was equipped with an electrosprayion source (ESI) operated in a positive or negative mode. The massspectrometer was scanned between m/z 90-900 with a scan time from 0.5 to1.0 s. The column used was a Kinetex EVO, 2.6 μm, 3.0×50 mm. A lineargradient was applied, starting at 90% A (A: 0.05% NH₄HCO₃ in water) andending at 95% B (B: MeCN) over 2.7 min with a total run time of 3.0 min.The column temperature was at 40° C. with a flow rate of 1.3 mL/min.

Liquid Chromatography-Mass Spectrometry Method I:

LCMS analyses were performed on a SHIMADZU LCMS consisting of an UFLC20-AD and LCMS 2020 MS detector. The Diode Array Detector was scannedfrom 190-400 nm. The mass spectrometer was equipped with an electrosprayion source (ESI) operated in a positive or negative mode. The massspectrometer was scanned between m/z 90-900 with a scan time from 0.5 to1.0 s. The column used was an Ascentis Express C18, 2.7 μm, 2.1×50 mm. Alinear gradient was applied, starting at 90% A (A: 0.10% formic acid inwater) and ending at 100% B (B: 0.10% formic acid in MeCN) over 1.70 minwith a total run time of 2.0 min. The column temperature was at 45° C.with a flow rate of 1.0 mL/min.

Liquid Chromatography-Mass Spectrometry Method J:

LCMS analyses were performed on a SHIMADZU LCMS consisting of an UFLC20-AD and LCMS 2020 MS detector. The Diode Array Detector was scannedfrom 190-400 nm. The mass spectrometer was equipped with an electrosprayion source (ESI) operated in a positive or negative mode. The massspectrometer was scanned between m/z 90-900 with a scan time from 0.5 to1.0 s. The column used was an Ascentis Express C18, 2.7 μm, 2.1×50 mm. Alinear gradient was applied, starting at 90% A (A: 0.10% formic acid inwater) and ending at 95% B (B: 0.10% formic acid in MeCN) over 2.70 minwith a total run time of 3.0 min. The column temperature was at 45° C.with a flow rate of 1.0 mL/min.

Liquid Chromatography-Mass Spectrometry Method K:

LCMS analyses were performed on a SHIMADZU LCMS consisting of an UFLC20-AD and LCMS 2020 MS detector. The Diode Array Detector was scannedfrom 190-400 nm. The mass spectrometer was equipped with an electrosprayion source (ESI) operated in a positive or negative mode. The massspectrometer was scanned between m/z 90-900 with a scan time from 0.5 to1.0 s. The column used was an Ascentis Express C18, 2.7 μm, 3.0×50 mm. Alinear gradient was applied, starting at 95% A (A: 0.05% TFA in water)and ending at 100% B (B: 0.05% TFA in MeCN) over 1.6 min with a totalrun time of 2.0 min. The column temperature was at 40° C. with a flowrate of 1.5 mL/min.

Liquid Chromatography-Mass Spectrometry Method L:

LCMS analyses were performed on a SHIMADZU LCMS consisting of an UFLC20-AD and LCMS 2020 MS detector. The Diode Array Detector was scannedfrom 190-400 nm. The mass spectrometer was equipped with an electrosprayion source (ESI) operated in a positive or negative mode. The massspectrometer was scanned between m/z 90-900 with a scan time from 0.5 to1.0 s. The column used was an Ascentis Express C18, 2.7 μm, 3.0×50 mm. Alinear gradient was applied, starting at 95% A (A: 0.05% TFA in water)and ending at 100% B (B: 0.05% TFA in MeCN) over 2.6 min with a totalrun time of 3.0 min. The column temperature was at 40° C. with a flowrate of 1.5 mL/min.

Liquid Chromatography-Mass Spectrometry Method M:

LCMS analyses were performed on a SHIMADZU LCMS consisting of an UFLC20-AD and LCMS 2020 MS detector. The Diode Array Detector was scannedfrom 190-400 nm. The mass spectrometer was equipped with an electrosprayion source (ESI) operated in a positive or negative mode. The massspectrometer was scanned between m/z 90-900 with a scan time from 0.5 to1.0 s. The column used was an Kinetex XB-C18, 2.6 μm, 3.0×50 mm. Alinear gradient was applied, starting at 95% A (A: 0.05% TFA in water)and ending at 100% B (B: 0.05% TFA in MeCN) over 2.8 min with a totalrun time of 3.0 min. The column temperature was at 40° C. with a flowrate of 1.5 mL/min.

Liquid Chromatography-Mass Spectrometry Method N:

LCMS analyses were performed on a SHIMADZU LCMS consisting of an UFLC20-AD and LCMS 2020 MS detector. The Diode Array Detector was scannedfrom 190-400 nm. The mass spectrometer was equipped with an electrosprayion source (ESI) operated in a positive or negative mode. The massspectrometer was scanned between m/z 90-900 with a scan time from 0.5 to1.0 s. The column used was an Ascentis Express C18, 2.7 μm, 3.0×50 mm. Alinear gradient was applied, starting at 95% A (A: 0.05% TFA in water)and ending at 100% B (B: 0.05% TFA in MeCN) over 1.7 min with a totalrun time of 2.0 min. The column temperature was at 40° C. with a flowrate of 1.5 mL/min.

Liquid Chromatography-Mass Spectrometry Method O:

The column used was an Agilent Poroshell HPH-C18, 2.7 μm, 3.0×50 mm. Alinear gradient was applied, starting at 95% A (A: 0.05% NH₄HCO₃ inwater) and ending at 95% B (B: 0.05% NH₄HCO₃ in MeCN) over 2.7 min witha total run time of 3 min. The column temperature was at 45° C. with aflow rate of 1.5 mL/min.

Liquid Chromatography-Mass Spectrometry Method P:

The column used was an Ascentis Express C18, 3.5 μm, 4.6×50 mm. A lineargradient was applied, starting at 90% A (A: 0.05% NH₄HCO₃ in water) andending at 95% B (B: 0.05% NH₄HCO₃ in MeCN) over 5.2 min with a total runtime of 5.6 min. The column temperature was at 40° C. with a flow rateof 1.5 mL/min.

Liquid Chromatography-Mass Spectrometry Method Q:

The column used was an Agilent Poroshell HPH-C18, 2.7 μm, 3.0×50 mm. Alinear gradient was applied, starting at 95% A (A: 0.05% NH₄HCO₃ inwater) and ending at 95% B (B: 0.05% NH₄HCO₃ in MeCN) over 4.7 min witha total run time of 5.0 min. The column temperature was at 40° C. with aflow rate of 1.5 mL/min.

Liquid Chromatography-Mass Spectrometry Method R:

The column used was an Agilent Poroshell HPH-C18, 2.7 μm, 3.0×50 mm. Alinear gradient was applied, starting at 95% A (A: 0.05% NH₄HCO₃ inwater) and ending at 95% B (B: 0.05% NH₄HCO₃ in MeCN) over 1.8 min witha total run time of 2.0 min. The column temperature was at 40° C. with aflow rate of 1.5 mL/min.

Liquid Chromatography-Mass Spectrometry Method S:

The column used was an Ascentis Express C18, 2.7 μm, 3.0×50 mm. A lineargradient was applied, starting at 95% A (A: 0.05% TFA in water) andending at 100% B (B: 0.05% TFA in MeCN) over 1.8 min with a total runtime of 2.0 min. The column temperature was at 40° C. with a flow rateof 1.5 mL/min.

Liquid Chromatography-Mass Spectrometry Method T:

The column used was an Ascentis Express C18, 2.7 μm, 3.0×50 mm. A lineargradient was applied, starting at 95% A (A: 0.05% TFA in water) andending at 100% B (B: 0.05% TFA in MeCN) over 2.7 min with a total runtime of 3.0 min. The column temperature was at 40° C. with a flow rateof 1.5 mL/min.

Liquid Chromatography-Mass Spectrometry Method U:

The column used was an Acquity UPLC™ BEH, C18 column (50×2.1 mm, 1.7 μmparticle size), column temperature 40° C., mobile phase: A—10 mM aqueousammonium bicarbonate solution adjusted to pH 10 with aqueous ammoniasolution/B-CH3CN, flow rate: 1.0 mL/min, runtime=2.0 min, gradient: t=0min 3% B, t=1.5 min 99.9% B, t=1.9 min 99.9% B, t=2.0 min 3% B, stoptime 2.0 min. Positive ES 100-1000, Negative ES 100-1000, UV detectionDAD 210-350 nm.

Liquid Chromatography-Mass Spectrometry Method V:

The column used was a Shim-pack XR-ODS, 2.2 μm, 3.0×50 mm. A lineargradient was applied, starting at 95% A (A: 0.05% TFA in water) andending at 100% B (B: 0.05% TFA in MeCN) over 4.2 min with a total runtime of 5.3 min. The column temperature was at 40° C. with a flow rateof 1.0 mL/min.

Liquid Chromatography-Mass Spectrometry Method W:

The column used was an Shim-pack XR-ODS, 2.2 μm, 3.0×50 mm. A lineargradient was applied, starting at 95% A (A: 0.05% TFA in water) andending at 100% B (B: 0.05% TFA in MeCN) over 4.2 min with a total runtime of 5.3 min. The column temperature was at 40° C. with the flow rateof 1.0 mL/min.

Liquid Chromatography-Mass Spectrometry Method X:

The column used was an Ascentis Express C18, 2.7 m, 3.0×50 mm. A lineargradient was applied, starting at 95% A (A: 0.05% TFA in water) andending at 95% B (B: 0.05% TFA in MeCN) over 4.1 min with a total runtime of 5.3 min. The column temperature was at 40° C. with the flow rateof 1.5 mL/min.

Liquid Chromatography-Mass Spectrometry Method Y:

The column used was an Poroshell HPH-C18, 2.7 μm, 3.0×50 mm. A lineargradient was applied, starting at 95% A (A: 0.05% NH₄HCO₃ in water) andending at 95% B (B: 0.05% NH₄HCO₃ in MeCN) over 1.8 min with a total runtime of 2 min. The column temperature was at 45° C. with the flow rateof 1.5 mL/min.

HPLC analyses were performed on a SHIMADZU UFLC with two LC20 AD pumpand a SPD-M20A Photodiiode Array Detector. The column used was anXBridge C18, 3.5 μm, 4.6×100 mm. A linear gradient was applied, startingat 90% A (A: 0.05% TFA in water) and ending at 95% B (B: 0.05% TFA inMeCN) over 10 min with a total run time of 15 min. The columntemperature was at 40° C. with the flow rate of 1.5 mL/min. The DiodeArray Detector was scanned from 200-400 nm.

Thin layer chromatography (TLC) was performed on Alugram® (Silica gel 60F254) from Mancherey-Nagel and UV was typically used to visualize thespots. Additional visualization methods were also employed in somecases. In these cases the TLC plate was developed with iodine (generatedby adding approximately 1 g of I₂ to 10 g silica gel and thoroughlymixing), ninhydrin (available commercially from Aldrich), or Magic Stain(generated by thoroughly mixing 25 g (NH₄)₆Mo₇I₂₄.4H₂O, 5 g(NH₄)₂Ce(IV)(NO₃)₆ in 450 mL water and 50 mL concentrated H₂SO₄) tovisualize the compound. Flash chromatography was performed using 40-63μm (230-400 mesh) silica gel from Silicycle following analogoustechniques to those disclosed in Still, W. C.; Kahn, M.; and Mitra, M.Journal of Organic Chemistry, 1978, 43, 2923. Typical solvents used forflash chromatography or thin layer chromatography were mixtures ofchloroform/methanol, dichloromethane/methanol, ethyl acetate/methanoland hexanes/ethyl acetate.

Analytical Methods

¹H Nuclear magnetic resonance (NMR) spectroscopy was carried out using aBruker Avance III equipped with a BBFO 300 MHz probe operating at 300MHz or one of the following instruments: a Bruker Avance 400 instrumentequipped with probe DUAL 400 MHz S1, a Bruker Avance 400 instrumentequipped with probe 6 S1 400 MHz 5 mm ¹H-¹³C ID, a Bruker Avance III 400instrument with nanobay equipped with probe Broadband BBFO 5 mm direct,a Bruker Mercury Plus 400 NMR Spectrometer equipped with a Bruker 400BBO probe all operating at 400 MHz. The spectra were acquired in thestated solvent at around room temperature unless otherwise stated. Inall cases, NMR data were consistent with the proposed structures. Flashchromatography was performed using 40-63 μm (230-400 mesh) silica gelfrom Silicycle following analogous techniques to those disclosed inStill, W. C.; Kahn, M.; and Mitra, M. Journal of Organic Chemistry,1978, 43, 2923.

Compound Preparation

Where the preparation of starting materials is not described, these arecommercially available, known in the literature, or readily obtainableby those skilled in the art using standard procedures. Where it isstated that compounds were prepared analogously to earlier examples orintermediates, it will be appreciated by the skilled person that thereaction time, number of equivalents of reagents and temperature can bemodified for each specific reaction and that it may be necessary ordesirable to employ different work-up or purification techniques. Wherereactions are carried out using microwave irradiation, the microwaveused is a Biotage Initiator. The actual power supplied varies during thecourse of the reaction in order to maintain a constant temperature.

Example 1:5-Benzyl-N-(2-chloro-4-methyl-5-oxo-4H,5H,6H,7H,8H-thieno[3,2-b]azepin-6-yl)-1,2-oxazole-3-carboxamide

Step 1: Preparation ofN-[4,5,6,7-Tetrahydro-1-benzothiophen-4-ylidene]hydroxylamine

A solution of hydroxylamine hydrochloride (4.56 g, 65.7 mmol) in 5 Nsodium acetate solution (120 mL) was added to a solution of6,7-dihydro-1-benzothiophen-4(5H)-one (2.00 g, 13.1 mmol) in EtOH (200mL). The reaction mixture was heated to 100° C. and stirred for 2 h.Volatiles were removed under reduced pressure and the crude product wasdissolved in water and extracted with EtOAc. The organic portion waswashed with brine, dried over Na₂SO₄, filtered and concentrated underreduced pressure. The crude product was purified by columnchromatography (cyclohexane-EtOAc, 100:0 to 50:50) to give the titlecompound (1.10 g, 51%). ¹H NMR (400 MHz, CDCl₃) δ 7.76-7.42 (m, 1H),7.30 (d, J=5.3 Hz, 1H), 7.09 (d, J=5.3 Hz, 1H), 2.89 (t, J=6.1 Hz, 2H),2.82-2.77 (m, 2H), 2.02 (quin, J=6.3 Hz, 2H). LC-MS (Method A):m/z=168.0 [M+H]⁺, 0.83 min.

Step 2: Preparation of 4H,5H,6H,7H,8H-Thieno[3,2-b]azepin-5-one

Phosphorus pentoxide (11.3 g, 79.5 mmol) was added to methanesulfonicacid (10.9 g, 113.6 mmol) and the mixture was stirred for 2 h.N-[4,5,6,7-Tetrahydro-1-benzothiophen-4-ylidene]hydroxylamine (1.10 g,6.58 mmol) was then added to the above stirred solution, which had beenpreviously warmed to 100° C. After stirring for 4 h at 110° C., thereaction was cooled and quenched carefully by adding sat. NaHCO₃solution. The mixture was extracted with chloroform. The combinedorganic portions were washed with sat. NaHCO₃ solution and water, driedover Na₂SO₄, filtered and concentrated under reduced pressure. The crudeproduct was purified by column chromatography (cyclohexane-EtOAc, 80:20to 0:100) to give the desired compound (450 mg, 41%). ¹H NMR (400 MHz,CDCl₃) δ 7.90-7.69 (m, 1H), 7.08 (d, J=5.3 Hz, 1H), 6.64 (d, J=5.3 Hz,1H), 3.00 (t, J=6.9 Hz, 2H), 2.67-2.60 (m, 2H), 2.26-2.14 (m, 2H).

Step 3: Preparation of 2-Chloro-4H,5H,6H,7H,8H-thieno[3,2-b]azepin-5-one

N-Chlorosuccinimide (356 mg, 2.68 mmol) was added to a solution of4H,5H,6H,7H,8H-thieno[3,2-b]azepin-5-one (450 mg, 2.69 mmol) in DMF (10mL). The reaction was warmed to 50° C. and stirred at that temperaturefor 16 h. The reaction was diluted with EtOAc, washed twice with sat.NH₄Cl solution, dried over Na₂SO₄, filtered and concentrated underreduced pressure. The crude product was purified by columnchromatography (cyclohexane/EtOAc, 100:0 to 0:100) to give the titlecompound (190 mg, 35%). ¹H NMR (400 MHz, CDCl₃) δ 7.73 (br.s, 1H), 6.50(s, 1H), 2.89 (t, J=6.9 Hz, 2H), 2.66-2.59 (m, 2H), 2.23-2.13 (m, 2H).LC-MS (Method A): m/z=202.1 [M+H]⁺, 0.84 min.

Step 4: Preparation of2-Chloro-6-iodo-4H,5H,6H,7H,8H-thieno[3,2-b]azepin-5-one

Iodotrimethylsilane (264 μL, 0.189 mmol) was added to a solution of2-chloro-4H,5H,6H,7H,8H-thieno[3,2-b]azepin-5-one (190 mg, 0.945 mmol)and TMEDA (430 μL, 22.8 mmol) in CH₂Cl₂ (3 mL) which had been pre-cooledto −10° C. The reaction was stirred at −10° C. for 30 min. Powderediodine (360 mg, 1.42 mmol) was added. The mixture was stirred at −10° C.for 1 h, allowed to reach room temperature over 1.5 h, stirred for afurther 30 min and quenched with 1 M Na₂S₂O₃ solution. The layers wereseparated and the aqueous portion was extracted twice with CH₂Cl₂. Thecombined organic portions were dried over Na₂SO₄, filtered andconcentrated under reduced pressure. The crude product was trituratedwith CH₂Cl₂ to yield the title compound (135 mg, 44%). ¹H NMR (400 MHz,DMSO-d₆) δ 10.03 (s, 1H), 6.69 (s, 1H), 4.99-4.91 (m, 1H), 3.15-3.06 (m,1H), 2.95 (ddd, J=17.4, 11.9, 5.5 Hz, 1H), 2.19-208 (m, 1H), 1.88 (dddd,J=14.9, 11.9, 5.1, 2.0 Hz, 1H).

Step 5: Preparation of2-Chloro-6-iodo-4-methyl-4H,5H,6H,7H,8H-thieno[3,2-b]azepin-5-one

Iodomethane (29 μL, 0.460 mmol) was added to a mixture of2-chloro-6-iodo-4H,5H,6H,7H,8H-thieno[3,2-b]azepin-5-one (135 mg, 0.418mmol) and Cs₂CO₃ (205 mg, 0.627 mmol) in DMF (6 mL). The reaction wasstirred at room temperature for 4 h, cooled to 4° C. and stirred at thattemperature for 36 h. Further iodomethane (29 μL, 0.460 mmol) was addedand the mixture was stirred at room temperature for 5 h. EtOAc was addedand the organic portion was washed twice with 0.5 M HCl solution, driedover Na₂SO₄, filtered and concentrated under reduced pressure. The crudeproduct was purified by column chromatography (cyclohexane/EtOAc, 100:0to 50:50) to give the title compound (72 mg, 51%). ¹H NMR (400 MHz,DMSO-d₆) δ 7.28 (s, 1H), 4.82 (dd, J=9.2, 6.7 Hz, 1H), 3.17 (s, 3H),2.90-2.56 (m, 4H). LC-MS (Method A): m/z=342.0 [M+H]⁺, 1.10 min.

Step 6: Preparation of6-Azido-2-chloro-4-methyl-4H,5H,6H,7H,8H-thieno[3,2-b]azepin-5-one

A mixture of2-chloro-6-iodo-4-methyl-4H,5H,6H,7H,8H-thieno[3,2-b]azepin-5-one (70mg, 0.205 mmol) and NaN₃ (20 mg, 0.307 mmol) in DMF (2 mL) was stirredat 33° C. for 2 h. EtOAc was added and the organic portion was washedtwice with 0.5 M HCl solution, dried over Na₂SO₄, filtered andconcentrated under reduced pressure to afford the title compound (52mg), which was directly progressed to the next step. ¹H NMR (400 MHz,DMSO-d₆) δ 7.28 (s, 1H), 4.11 (dd, J=11.7, 7.4 Hz, 1H), 3.20 (s, 3H),2.88-2.77 (m, 2H), 2.53-2.40 (m, 1H), 2.28-2.13 (m, 1H). LC-MS (MethodA): m/z=257.1 [M+H]⁺, 1.04 min.

Step 7. Preparation of6-Amino-2-chloro-4-methyl-4H,5H,6H,7H,8H-thieno[3,2-b]azepin-5-one

A mixture of6-azido-2-chloro-4-methyl-4H,5H,6H,7H,8H-thieno[3,2-b]azepin-5-one (52mg) and triphenylphosphine (60 mg, 0.229 mg) in 3:1 THF-H₂O (2 mL) wasstirred at room temperature for 18 h. The reaction was diluted withEtOAc and washed twice with water. The organic portion was dried overNa₂SO₄, filtered and concentrated under reduced pressure. The crudeproduct was purified by column chromatography (cyclohexane/EtOAc, 60:40)to afford the title compound (37 mg, 85% purity). ¹H NMR (400 MHz,DMSO-d₆) δ 7.25 (s, 1H), 3.37-3.28 (m, 1H), 3.16 (s, 3H), 2.71-2.64 (m,2H), 2.37-2.26 (m, 1H), 1.90-1.77 (m, 1H), 1.66 (br. s, 2H). LC-MS(Method A): m/z=231.1 [M+H]⁺, 0.41 min.

Amide Coupling Procedure A Step 8: Preparation and Separation of5-Benzyl-N-(2-chloro-4-methyl-5-oxo-4H,5H,6H,7H,8H-thieno[3,2-b]azepin-6-yl)-1,2-oxazole-3-carboxamide

A solution of6-amino-2-chloro-4-methyl-4H,5H,6H,7H,8H-thieno[3,2-b]azepin-5-one (27mg, ˜85% purity), HBTU (39.6 mg, 0.104 mmol), 1-hydroxybenzotriazole (14mg, 0.104 mmol), DIPEA (45 μL, 0.261 mmol) and5-benzyl-1,2-oxazole-3-carboxylic acid (19 mg, 0.092 mmol) in DMF (3.5mL) was stirred at room temperature for 4 h. EtOAc was added and theorganic portion was washed twice with sat. NH₄Cl solution, dried overNa₂SO₄, filtered and concentrated under reduced pressure. The crudeproduct was purified by column chromatography (cyclohexane/EtOAc, 100:0to 50:50) to give the title compound as a mixture of enantiomers. Thismixture was resolved by chiral HPLC on a Whelk O-1 (R,R) (25×2.0 cm), 10m column using a mobile phase of n-hexane/(EtOH/MeOH/CH₂Cl₂45/45/10+0.1% isopropylamine) 20/80% v/v to afford the two titlecompounds as separated enantiomers.

First eluting enantiomer, Enantiomer 1: ¹H NMR (400 MHz, CDCl₃) δ 7.76(d, J=7.5 Hz, 1H), 7.42-7.20 (m, 5H), 6.80 (s, 1H), 6.34 (s, 1H), 4.81(dt, J=11.2, 7.2 Hz, 1H), 4.13 (s, 2H), 3.31 (s, 3H), 3.02-2.78 (m, 2H),2.77-2.66 (m, 1H), 2.23-2.09 (m, 1H). LC-MS (Method A): m/z=416.2[M+H]⁺, 1.16 min. e.e.>99.5% as determined on a Whelk O-1 (R,R) (25×2.0cm), 10 m column using a mobile phase of n-hexane/(EtOH/MeOH/CH₂Cl₂45/45/10+0.1% isopropylamine) 20/80% v/v.

Second eluting enantiomer, Enantiomer 2: ¹H NMR (400 MHz, CDCl₃) δ7.82-7.71 (m, 1H), 7.39-7.23 (m, 5H), 6.80 (s, 1H), 6.34 (s, 1H), 4.81(dt, J=11.2, 7.1 Hz, 1H), 4.13 (s, 2H), 3.31 (s, 3H), 3.00-2.78 (m, 2H),2.76-2.66 (m, 1H), 2.21-2.10 (m, 1H). LC-MS (Method A): m/z=416.2[M+H]⁺, 1.16 min. e.e.=98.4% as determined on a Whelk O-1 (R,R) (25×2.0cm), 10 m column using a mobile phase of n-hexane/(EtOH/MeOH/CH₂Cl₂45/45/10+0.1% isopropylamine) 20/80% v/v.

Example2:5-benzyl-N-(5-fluoro-1-methyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-3-yl)isoxazole-3-carboxamide

Step 1: Preparation of(2R)-4-(2-aminophenyl)-2-[[(tert-butoxy)carbonyl]amino]-4-oxobutanoicacid

Di-tert-butyl dicarbonate (7.19 g, 32.9 mmol) was added to a solution ofthe sulphate of (2R)-2-amino-4-(2-aminophenyl)-4-oxobutanoic acid (9.18g, 29.9 mmol) and triethylamine (12.1 g, 119.6 mmol) in dioxane (50 mL)under nitrogen atmosphere with stirring. The resulting mixture wasstirred overnight at room temperature. The reaction mixture wasconcentrated under vacuum to afford the title compound (9.18 g crude).LC-MS (Method C): m/z=309.1 [M+H]⁺, 1.307 min.

Step 2: Preparation of (R)-tert-butyl(2,5-dioxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-3-yl)carbamate

2-(7-Aza-1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluroniumhexafluorophosphate (13.6 g, 35.9 mmol) and ethyldiisopropylamine (11.6g, 89.7 mmol) were added to a stirred solution of(2R)-4-(2-aminophenyl)-2-[[(tert-butoxy)carbonyl]amino]-4-oxobutanoicacid (9.21 g, 29.8 mmol) in N,N-dimethylformamide (50 mL). The resultingsolution was stirred for 2 hours at room temperature. The reactionmixture was diluted with water (50 mL), and extracted with ethyl acetate(3×40 mL). The combined organic layers were dried over anhydrous sodiumsulfate, filtered and concentrated under vacuum. The residue waspurified by column chromatography (ethyl acetate/petroleum ether, 1/6)to afford the title compound (2.2 g, 25%). LC-MS (Method C): m/z=291.1[M+H]⁺, 1.298 min.

Step 3: Preparation of tert-butyl(1-methyl-2,5-dioxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-3-yl)carbamate

Iodomethane (1.08 g, 7.60 mmol) was added dropwise to a stirred solutionof (R)-tert-butyl(2,5-dioxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-3-yl)carbamate (2.01 g,6.89 mmol) and cesium carbonate (2.47 g, 7.58 mmol) inN,N-dimethylformamide (20 mL) with stirring. The resulting solution wasstirred for 3 hours at room temperature. Water (10 mL) was added toquench the reaction. The reaction mixture was extracted with ethylacetate (3×50 mL). The combined organic layers were concentrated undervacuum. The residue was purified by column chromatography (ethylacetate/petroleum ether, 1/10) to afford the title compound (1.20 g,57%). LC-MS (Method G): m/z=305.0 [M+H]⁺, 1.004 min.

Step 4: Preparation of tert-butyl(5-hydroxy-1-methyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-3-yl)carbamate

tert-Butyl(1-methyl-2,5-dioxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-3-yl)carbamate(506.0 mg, 1.66 mmol) in methanol (20 mL) was hydrogenated in thepresence of 10% palladium on carbon (50.0 mg) under hydrogen atmosphere(2-3 atmospheres). The resulting solution was stirred overnight at roomtemperature. The solids were removed by filtration and the filtrate wasevaporated under vacuum to afford the title compound (0.5 g crude).LC-MS (Method C): m/z=307.2 [M+H]⁺, 1.273 min.

Step 5: Preparation of tert-butylN-[5-fluoro-1-methyl-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepin-3-yl]carbamate

Diethylaminosulfur trifluoride (40.3 mg, 0.25 mmol) was added to asolution of tert-butyl(5-hydroxy-1-methyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-3-yl)carbamate(30.6 mg, 0.10 mmol) in dichloromethane (2 mL) under nitrogen atmosphereat 0° C. The resulting solution was stirred for 3 hours at 0° C. Thereaction was quenched with saturated aqueous sodium bicarbonate (2 mL)and extracted with ethyl acetate (3×5 mL). The combined organic layerswere dried over anhydrous sodium sulfate, filtered and concentratedunder vacuum. The residue was purified by column chromatography (ethylacetate/petroleum ether, 1/4) to afford the title compound (25 mg, 81%).LC-MS (Method K): m/z=208.9 [M-Boc+H]⁺, 0.946 min.

Step 6: Preparation of3-amino-5-fluoro-1-methyl-2,3,4,5-tetrahydro-1H-1-benzazepin-2-onehydrochloride

A solution of tert-butylN-[5-fluoro-1-methyl-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepin-3-yl]carbamate(25.0 mg, 0.08 mmol) in 4 N hydrogen chloride in dioxane (2 mL) wasstirred for 0.5 hour at room temperature. The resulting mixture wasconcentrated under vacuum to afford the title compound (20 mg crude).LC-MS (Method K): m/z=208.9 [M+H]⁺, 0.555 min

Step 7. Preparation of5-benzyl-N-(5-fluoro-1-methyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-3-yl)isoxazole-3-carboxamide

A solution of 5-benzyl-1,2-oxazole-3-carboxylic acid (16.0 mg, 0.08mmol) in N,N-dimethylformamide (2 mL) was added to a stirred solution of2-(7-aza-1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluroniumhexafluorophosphate (45.6 mg, 0.12 mmol), ethyldiisopropylamine (38.7mg, 0.30 mmol),3-amino-5-fluoro-1-methyl-2,3,4,5-tetrahydro-1H-1-benzazepin-2-onehydrochloride (20.0 mg, 0.08 mmol) in N,N-dimethylformamide (10 mL). Theresulting solution was stirred for 2 hours at room temperature and thendiluted with water (10 mL). The reaction mixture was extracted withethyl acetate (3×20 mL). The combined organic layers were dried overanhydrous sodium sulfate, filtered and concentrated under vacuum. Thecrude product was purified by reverse phase chromatography using anXbridge Phenyl OBD 5 μm, 19×150 mm column; mobile phase, water (10mmol/L NH₄HCO₃) and ACN (50.0% ACN to 70.0% in 7 min) to afford thetitle compound. ¹H NMR (400 MHz, DMSO-d₆) δ 8.85 (d, J=7.6 Hz, 1H),7.59-7.52 (m, 2H), 7.44-7.26 (m, 7H), 6.54 (s, 1H), 5.76 (dd, J=4.4,48.8 Hz, 1H), 4.52-4.45 (m, 1H), 4.22 (s, 2H), 3.25 (s, 3H), 2.74-2.71(m, 1H), 2.66-2.61 (m, 1H). LC-MS (Method L): m/z=394.1 [M+H]⁺, 1.482min.

Amide Coupling Procedure B Step 8: Preparation of5-benzyl-N-(5-fluoro-1-methyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-3-yl)isoxazole-3-carboxamide(First Eluting Isomer, Example 2A) and5-benzyl-N-(5-fluoro-1-methyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-3-yl)isoxazole-3-carboxamide(Second Eluting Isomer Example 2B)

3-Amino-5-fluoro-1-methyl-2,3,4,5-tetrahydro-1H-1-benzazepin-2-one (30mg, 0.140 mmol) was added to a stirring solution of5-benzyl-1,2-oxazole-3-carboxylic acid (32.3 mg, 0.159 mmol),N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uroniumhexafluorophospate (65.7 mg, 0.173 mmol) and N,N-diisopropylethylamine(55.7 mg, 0.432 mmol) in N,N-dimethylformamide (5 mL). After stirringfor 3 hours at room temperature, the reaction mixture was diluted withwater (10 mL) and extracted with ethyl acetate (3×10 mL). The combinedorganic layers were washed with brine, dried over anhydrous sodiumsulfate, filtered and concentrated under reduced pressure. The crudeproduct was purified by Prep-HPLC with the following conditions: Column,XBridge Prep C18 OBD Column, 5 μm, 19×150 mm; mobile phase, water (0.05%TFA) and ACN (45.0% ACN to 70.0% over 7 min); Detector, UV 254/220 nm toafford the title compounds:

Example 2A, first eluting isomer: ¹H NMR (300 MHz, CD₃OD) δ 8.53 (d,J=6.9 Hz, 1H), 7.55-7.50 (m, 1H), 7.50-7.42 (m, 1H), 7.40-7.14 (m, 7H),6.36 (s, 1H), 5.79-5.28 (m, 1H), 4.73-4.48 (m, 1H), 4.13 (s, 2H), 3.32(s, 3H), 2.91-2.72 (m, 1H), 2.64-2.40 (m, 1H). LC-MS (Method D):m/z=394.1 [M+H]⁺, 2.075 min.

Example 2B, second eluting isomer: ¹H NMR (300 MHz, DMSO-d6) δ 8.84 (d,J=7.5 Hz, 1H), 7.51-7.39 (m, 4H), 7.38-7.25 (m, 5H), 6.52 (s, 1H),5.98-5.28 (m, 1H), 4.34-4.25 (m, 1H), 4.21 (s, 2H), 3.29 (s, 3H),2.91-2.83 (m, 1H), 2.42-2.32 (m, 1H). LC-MS (Method D): m/z=394.1[M+H]⁺, 2.164 min.

Example 3:(S)-5-benzyl-N-(1-methyl-5-methylene-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-3-yl)isoxazole-3-carboxamide

Step 1: Preparation of(2S)-4-(2-aminophenyl)-2-[[(tert-butoxy)carbonyl]amino]-4-oxobutanoicacid

Di-tert-butyl dicarbonate (0.96 g, 4.39 mmol) was added to a solution ofthe sulphate of (2S)-2-amino-4-(2-aminophenyl)-4-oxobutanoic acid (1.22g, 4.00 mmol) and triethylamine (1.21 g, 11.98 mmol) in dioxane (10 mL)under nitrogen atmosphere with stirring. The resulting mixture wasstirred for 4 hours at room temperature. The reaction mixture wasconcentrated under vacuum to afford the title compound (1.22 g crude).LC-MS (Method K): m/z=309.1 [M+H]⁺, 1.549 min.

Step 2: Preparation of tert-butylN-[(3S)-2,5-dioxo-2,3,4,5-tetrahydro-1H-1-benzazepin-3-yl]carbamate

2-(7-Aza-1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluroniumhexafluorophosphate (1.82 g, 4.80 mmol) and ethyldiisopropylamine (1.55g, 11.99 mmol) were added to a stirred solution of(2S)-4-(2-aminophenyl)-2-[[(tert-butoxy)carbonyl]amino]-4-oxobutanoicacid (1.23 g, 4.00 mmol) in N,N-dimethylformamide (10 mL). The resultingsolution was stirred for 2 hours at room temperature. The reactionmixture was diluted with water (10 mL) and extracted with ethyl acetate(3×20 mL). The combined organic portions were dried over anhydroussodium sulfate, filtered and concentrated under reduced pressure toafford the title compound (850 mg). LC-MS (Method K): m/z=291.1 [M+H]⁺,0.850 min.

Step 3: Preparation of tert-butylN-[(3S)-1-methyl-2,5-dioxo-2,3,4,5-tetrahydro-1H-1-benzazepin-3-yl]carbamate

Iodomethane (118 mg, 0.83 mmol) was added dropwise to a stirred mixtureof tert-butylN-[(3S)-2,5-dioxo-2,3,4,5-tetrahydro-1H-1-benzazepin-3-yl]carbamate(220.0 mg, 0.76 mmol) and cesium carbonate (272 mg, 0.83 mmol) inN,N-dimethylformamide (20 mL). The resulting mixture was stirred for 6hours at room temperature before water (10 mL) was added to quench thereaction. The reaction mixture was extracted with ethyl acetate (3×20mL). The combined organic layers were dried over anhydrous sodiumsulfate, filtered and concentrated under vacuum. The residue waspurified by column chromatography (ethyl acetate/petroleum ether, 1/4)to provide the title compound (130 mg, 56%). LC-MS (Method K): m/z=305.0[M+H]⁺, 0.907 min.

Step 4: Preparation of tert-butylN-[(3S)-1-methyl-5-methylidene-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepin-3-yl]carbamate

A suspension of methyltriphenylphosphonium bromide (382 mg, 1.07 mmol)and sodium hydride (20.0 mg, 0.83 mmol) in tetrahydrofuran (2 mL) wasstirred for 1 h at 50° C. under nitrogen atmosphere. Then a solution oftert-butylN-[(3S)-1-methyl-2,5-dioxo-2,3,4,5-tetrahydro-1H-1-benzazepin-3-yl]carbamate(101.0 mg, 0.33 mmol) in tetrahydrofuran (2 mL) was added drop-wise tothe reaction mixture with stirring. The resulting solution was stirredovernight at room temperature. The reaction was then quenched by theaddition of saturated aqueous ammonium chloride (5 mL). The resultingsolution was extracted with ethyl acetate (3×10 mL) and the organiclayers were combined, dried over anhydrous sodium sulfate, filtered andconcentrated under vacuum. The residue was purified by columnchromatography (ethyl acetate/petroleum ether, 1/10) to provide thetitle compound (75 mg, 75%). LC-MS (Method C): m/z=303.2 [M+H]⁺, 1.531min.

Step 5: Preparation of(S)-3-amino-1-methyl-5-methylene-4,5-dihydro-1H-benzo[b]azepin-2(3H)-onehydrochloride

A solution of tert-butylN-[(3S)-1-methyl-5-methylidene-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepin-3-yl]carbamate(40.0 mg, 0.13 mmol) in hydrogen chloride in dioxane (4 N, 6 mL) wasstirred for 1 hour at room temperature. The reaction mixture wasconcentrated under vacuum to afford the title compound (25.2 mg crude).LC-MS (Method C): m/z=203.2 [M+H]⁺, 0.635 min.

Amide Coupling Procedure C Step 6: Preparation of(S)-5-benzyl-N-(1-methyl-5-methylene-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-3-yl)isoxazole-3-carboxamide

A solution of(S)-3-amino-1-methyl-5-methylene-4,5-dihydro-1H-benzo[b]azepin-2(3H)-onehydrochloride (25.4 mg, 0.10 mmol) in N,N-dimethylformamide (2 mL) wasadded to a stirred solution of 5-benzyl-1,2-oxazole-3-carboxylic acid(20 mg, 0.10 mmol), 1-hydroxybenzotriazole (16 mg, 0.12 mmol),1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (23 mg, 0.12 mmol),ethyldiisopropylamine (39 mg, 0.30 mmol) in N,N-dimethylformamide (8mL). The resulting solution was stirred for 1 hour at room temperature.The reaction mixture was diluted with water (5 mL) and extracted withethyl acetate (3×10 mL). The combined organic layers were dried overanhydrous sodium sulfate, filtered and concentrated under vacuum. Thecrude product was purified by reverse phase chromatography using anXbridge Phenyl OBD 5 μm, 19×150 mm column; mobile phase, water (10mmol/L NH₄HCO₃) and ACN (50.0% ACN to 70.0% in 7 min) to afford thetitle compound (17.8 mg, 44%) as a white solid. This compound wasfurther purified by chiral HPLC on a Chiralpak AS-H (25×2.0 cm), 5 mcolumn using a mobile phase of n-hexane/(2-propanol/MeOH 1/1+0.1%isopropylamine) 60/40% v/v to afford the title compound. ¹H NMR (400MHz, CDCl₃) δ 7.87 (d, J=6.8 Hz, 1H), 7.44-7.22 (m, 8H), 7.18 (d, J=7.8Hz, 1H), 6.33 (s, 1H), 5.25-5.20 (m, 1H), 5.14-5.08 (m, 1H), 4.91 (td,J=6.9, 12.1 Hz, 1H), 4.13 (s, 2H), 3.55 (tdd, J=2.9, 6.5, 15.7 Hz, 1H),3.39 (s, 3H), 2.84 (dd, J=12.0, 15.6 Hz, 1H). LC-MS (Method A):m/z=388.1 [M+H]⁺, 1.21 min. e.e.>99.5% as determined on a Chiralpak AS-H(25×0.46 cm), 5 m column using a mobile phase ofn-hexane/(2-propanol/MeOH 1/1+0.1% isopropylamine) 60/40% v/v.

Example 4:(S)-1-benzyl-4-chloro-5-methyl-N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-pyrazole-3-carboxamide

Step 1: Preparation of ethyl 4-chloro-5-methyl-1H-pyrazole-3-carboxylate

N-Chlorosuccinimide (0.81 g, 5.99 mmol) was added to a solution of ethyl5-methyl-1H-pyrazole-3-carboxylate (1.01 g, 6.49 mmol) inN,N-dimethylformamide (5 mL). The resulting solution was stirredovernight at room temperature. The reaction mixture was diluted withwater (20 mL) and extracted with ethyl acetate (3×20 mL). The combinedorganic layers were dried over anhydrous sodium sulfate, filtered andconcentrated under vacuum. The residue was purified by columnchromatography (ethyl acetate/petroleum ether, 1/5) to afford the titlecompound (0.81 g, 65%). LC-MS (Method C): m/z=230.1 [M+CH₃CN+H]⁺, 1.240min.

Step 2: Preparation of ethyl1-benzyl-4-chloro-5-methyl-1H-pyrazole-3-carboxylate

Sodium hydride (108 mg, 4.50 mmol) was added to a solution of ethyl4-chloro-5-methyl-1H-pyrazole-3-carboxylate (600 mg, 3.18 mmol) intetrahydrofuran (3 mL). After stirring for 1 h at 0° C., benzyl bromide(550 mg, 3.22 mmol) was added. The resulting mixture was stirred for 2hours at room temperature. After quenching with water (3 mL), thereaction mixture was extracted with ethyl acetate (2×3 mL). The combinedorganic layers were dried over anhydrous sodium sulfate, filtered andconcentrated under vacuum. The residue was purified by columnchromatography (ethyl acetate/petroleum ether, 1/1) to afford the titlecompound (500 mg, 56%). LC-MS (Method E): m/z=278.9 [M+H]⁺, 0.986 min.

Step 3: Preparation of1-benzyl-4-chloro-5-methyl-1H-pyrazole-3-carboxylic acid

Potassium hydroxide (80 mg, 1.43 mmol) was added to a solution of ethyl1-benzyl-4-chloro-5-methyl-1H-pyrazole-3-carboxylate (120 mg, 0.43 mmol)in methanol (1.5 mL) and water (0.5 mL). The resulting solution wasstirred overnight at room temperature. The reaction mixture wasconcentrated under vacuum and diluted with water (5 mL). 3 NHydrochloride acid was added to adjust the pH to 3. The resulting solidwas collected by filtration to afford the title compound (110 mg). LC-MS(Method F): m/z=251.0 [M+H]⁺, 1.323 min.

Step 4: Preparation of(S)-1-benzyl-4-chloro-5-methyl-N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-pyrazole-3-carboxamide

The crude material obtained using Amide Coupling Procedure B waspurified by reverse phase chromatography using an Xbridge Prep C18 5 μm,19×150 mm column; Mobile phase: Phase A: aqueous ammonium bicarbonate(0.05%); Phase B: acetonitrile; (20% to 80% in 12 min) to afford thetitle compound. ¹H-NMR (400 MHz, DMSO-d₆) δ 8.18 (d, J=7.9 Hz, 1H), 7.50(dd, J=7.6, 1.9 Hz, 1H), 7.43-7.14 (m, 8H), 5.46 (s, 2H), 4.83 (dt,J=11.5, 7.8 Hz, 1H), 4.56 (dd, J=11.5, 9.8 Hz, 1H), 4.42 (dd, J=9.8, 7.7Hz, 1H), 3.32 (s, 3H), 2.20 (s, 3H). LC-MS (Method E): m/z=425.0 [M+H]⁺,1.488 min.

Example 5:(S)-5-benzyl-N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)thiazole-2-carboxamide

Step 1: Preparation of ethyl 5-methylthiazole-2-carboxylate

Oxalyl chloride (5 mL, 50.0 mmol) was added to a stirring solution of5-methylthiazole-2-carboxylic acid (1.43 g, 10.0 mmol) indichloromethane (10 mL). The resulting solution was stirred for 2 hoursat room temperature and concentrated under vacuum. The residue wasquenched by the addition of ethanol (50 mL) and concentrated undervacuum. The residue was diluted with water (20 mL), and extracted withethyl acetate (3×20 mL). The combined organic layers were dried overanhydrous sodium sulfate, filtered and concentrated under vacuum toafford the title compound (1.6 g, 90%) as a white solid. LC-MS (MethodE): m/z=172 [M+H]⁺, 0.607 min.

Step 2: Preparation of ethyl 5-(bromomethyl)thiazole-2-carboxylate

N-Bromosuccinimide (900 mg, 5.0 mmol) was added to a solution of ethyl5-methylthiazole-2-carboxylate (850 mg, 5.0 mmol) in carbontetrachloride (20 mL). The reaction was initiated by benzoyl peroxide (1mg) and then heated at 75° C. and stirred for 16 hours. The reactionmixture was cooled to 0° C. and the solid was removed by filtration. Thefiltrate was diluted with water (20 mL) and then extracted with ethylacetate (3×20 mL). The combined organic layers were washed withsaturated aqueous sodium carbonate and brine, dried over sodium sulfate,filtered and concentrated under vacuum. The residue was purified bycolumn chromatography (ethyl acetate/hexane, 1/20) to afford the titlecompound (1.0 g, 80%). LC-MS (Method F): m/z=250, 252 [M+H]⁺, 1.490 min.

Step 3: Preparation of ethyl 5-benzylthiazole-2-carboxylate

A 50-mL round-bottomed flask was charged with ethyl5-(bromomethyl)thiazole-2-carboxylate (300 mg, 1.38 mmol), toluene (10mL), ethanol (5 mL), phenylboronic acid (100 mg, 2.00 mmol) and sodiumcarbonate (372 mg, 5.52 mmol). The reaction mixture was placed under anitrogen atmosphere and tetrakis(triphenylphosphine)palladium (147 mg,0.13 mmol) was added. The resulting solution was stirred at 85° C.overnight under nitrogen atmosphere and was then quenched by theaddition of water (20 mL). The resulting solution was extracted withethyl acetate (3×40 mL). The combined organic layers were washed withsaturated aqueous sodium carbonate and brine, dried over anhydroussodium sulfate, filtered and concentrated under vacuum. The residue waspurified by column chromatography (ethyl acetate/hexane, 1/15) to affordthe title compound (250 mg, 56%). LC-MS (Method C): m/z=248 [M+H]⁺,1.971 min.

Step 4: Preparation of 5-benzylthiazole-2-carboxylic acid

A solution of lithium hydroxide (5.4 mg, 2.02 mmol) in water (3 mL) wasadded to a solution of ethyl 5-benzylthiazole-2-carboxylate (100 mg,0.405 mmol) in tetrahydrofuran (9 mL). The resulting solution wasstirred for 2 hours at room temperature and diluted with water (10 mL).The pH value of the solution was adjusted to 3-4 with 1N aqueoushydrogen chloride. The resulting solution was extracted with ethylacetate (3×20 mL) and the combined organic layers were dried overanhydrous sodium sulfate, filtered and concentrated under vacuum toafford the title compound (80 mg, 76%). LC-MS (Method F): m/z=220[M+H]⁺, 0.790 min.

Step 5: Preparation of(S)-5-benzyl-N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)thiazole-2-carboxamide

The crude material obtained using Amide Coupling Procedure C waspurified by reverse phase chromatography using an Xbridge Prep C18 5 μm,19×150 mm column; Mobile phase: Phase A: aqueous ammonium bicarbonate(0.05%); Phase B: acetonitrile; (20% to 80% in 12 min) to afford thetitle compound. ¹H NMR (300 MHz, Chloroform-d) δ 8.12 (d, J=7.3 Hz, 1H),7.62 (s, 1H), 7.41-7.16 (m, 9H), 5.12-4.95 (m, 1H), 4.81-4.69 (m, 1H),4.37-4.21 (m, 1H), 4.19 (s, 2H), 3.46 (s, 3H). LC-MS (Method D): m/z=394[M+H]⁺, 2.232 min.

Example 6:(S)-1-benzyl-4-fluoro-5-methyl-N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-pyrazole-3-carboxamide

Step 1: Preparation of ethyl 4-fluoro-5-methyl-1H-pyrazole-3-carboxylate

Selectfluor (3.5 g, 9.9 mmol) was added to a solution of ethyl5-methyl-1H-pyrazole-3-carboxylate (1.01 g, 6.49 mmol) in acetonitrile(10 mL). The resulting solution was stirred overnight at 65° C. in anoil bath. The reaction mixture was cooled to room temperature andconcentrated under vacuum. The residue was diluted with water (10 mL)and extracted with ethyl acetate (2×10 mL). The combined organic layerswere dried over sodium sulfate, filtered and concentrated under vacuum.The residue was purified by column chromatography (ethylacetate/petroleum ether, 1/1) to afford the title compound (660 mg,59%). LC-MS (Method E): m/z=172.9 [M+H]⁺, 0.607 min.

Step 2: Preparation of ethyl1-benzyl-4-fluoro-5-methyl-1H-pyrazole-3-carboxylate

Sodium hydride (118 mg, 4.92 mmol) was added to a solution of ethyl4-fluoro-5-methyl-1H-pyrazole-3-carboxylate (600 mg, 3.49 mmol) intetrahydrofuran (3 mL). After stirring for 1 hour at 0° C., benzylbromide (595 mg, 3.48 mmol) was added. The resulting mixture was stirredfor 2 hours at room temperature. The reaction mixture was then quenchedwith water (20 mL) and extracted with ethyl acetate (2×20 mL). Thecombined organic layers were dried over anhydrous sodium sulfate,filtered and concentrated under vacuum. The residue was purified bycolumn chromatography (ethyl acetate/petroleum ether, 1/1) to afford thetitle compound (240 mg, 26%). LC-MS (Method C): m/z=263.1 [M+H]⁺, 1.490min.

Step 3: Preparation of1-benzyl-4-fluoro-5-methyl-1H-pyrazole-3-carboxylic acid

Potassium hydroxide (80 mg, 1.43 mmol) was added to a solution of ethyl1-benzyl-4-fluoro-5-methyl-1H-pyrazole-3-carboxylate (113 mg, 0.43 mmol)in methanol (1.5 mL), and water (0.5 mL). The resulting solution wasstirred 2 hours at room temperature. The resulting mixture wasconcentrated under vacuum and the residue was diluted with water (1.5mL). Hydrochloric acid (3N) was added to adjust the pH to 3. Theresulting solid was collected by filtration to afford the title compound(110 mg). LC-MS (Method E): m/z=235.1 [M+H]⁺, 1.257 min.

Step 4: Preparation of(S)-1-benzyl-4-fluoro-5-methyl-N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-pyrazole-3-carboxamide

The crude material obtained using Amide Coupling Procedure B waspurified by reverse phase chromatography using an Xbridge Prep C18 5 μm19×150 mm column; Mobile phase: Phase A: aqueous ammonium bicarbonate(0.05%); Phase B: acetonitrile; (20% to 80% in 12 min) to afford thetitle compound. ¹H-NMR (400 MHz, DMSO-d₆) δ 8.10 (d, J=8.0 Hz, 1H), 7.50(dd, J=7.6, 2.0 Hz, 1H), 7.43-7.20 (m, 6H), 7.20-7.13 (m, 2H), 5.39 (s,2H), 4.83 (dt, J=11.4, 7.8 Hz, 1H), 4.56 (dd, J=11.5, 9.8 Hz, 1H), 4.42(dd, J=9.8, 7.7 Hz, 1H), 3.32 (s, 3H), 2.16 (d, J=1.4 Hz, 3H). LC-MS(Method F): m/z=409.1 [M+H]⁺, 1.412 min.

Example 7:5-benzyl-N-((2S)-4-methyl-3-oxo-1,1a,2,3,4,8b-hexahydrobenzo[b]cyclopropa[d]azepin-2-yl)isoxazole-3-carboxamide

Step 1: Preparation of (Z)-tert-butyl(I-methyl-2-oxo-2,3-dihydro-1H-benzo[b]azepin-3-yl)carbamate

To a solution of tert-butyl(5-hydroxy-1-methyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-3-yl)carbamate(918.0 mg, 3.00 mmol) and triethylamine (909.0 mg, 9.00 mmol) indichloromethane (20 mL) was added dropwise a solution of methanesulfonylchloride (687 mg, 6.00 mmol) in dichloromethane (2 mL) at 0° C. Afterstirring overnight at room temperature, the reaction mixture wasquenched by the addition of water (10 mL) and extracted with ethylacetate (3×20 mL). The combined organic layers were dried over anhydroussodium sulfate and concentrated under vacuum.1,8-Diazabicyclo[5.4.0]undec-7-ene was added to the crude solid withstirring. The resulting solution was stirred for 1 hour at 90° C. Water(20 mL) was added to quench the reaction. The reaction mixture wasextracted with ethyl acetate (3×40 mL). The combined organic layers weredried over anhydrous sodium sulfate, filtered and concentrated undervacuum to afford the title compound (0.3 g crude). LC-MS (Method C):m/z=289.0 [M+H]⁺, 1.494 min.

Step 2: Preparation of tert-butylN-[7-methyl-6-oxo-7-azatricyclo[6.4.0.0-[2,4]]dodeca-1(8),9,11-trien-5-yl]carbamate

A solution of 1-methyl-1-nitrosourea (1.073 g, 10.41 mmol) in ether (10mL) was added to a solution of potassium hydroxide (1.166 g, 20.78 mmol)in water (1.75 mL) dropwise with stirring at 0° C. After stirring for 1hour at 0° C., the organic phase was separated to provide a solution ofdiazomethane (10 mL). To a solution of (Z)-tert-butyl(1-methyl-2-oxo-2,3-dihydro-1H-benzo[b]azepin-3-yl)carbamate (300.0 mg,1.04 mmol) in tetrahydrofuran (4 mL) was added the solution ofdiazomethane (10 ml) with stirring at 0° C. To this mixture was added asolution of palladium diacetate (23.3 mg, 0.10 mmol) in tetrahydrofuran(1 mL) dropwise with stirring at 0° C. The resulting mixture was stirredovernight at room temperature. The solids were removed by filtration andthe filtrate was concentrated under vacuum. The residue was purified bycolumn chromatography (ethyl acetate/petroleum ether, 1/5) to afford thetitle compound (50 mg, 16%). LC-MS (Method N): m/z=303.1 [M+H]⁺, 1.043min.

Step 3: Preparation of5-amino-7-methyl-7-azatricyclo[6.4.0.0-[2,4]]dodeca-1(8),9,11-trien-6-onehydrochloride

A solution of tert-butylN-[7-methyl-6-oxo-7-azatricyclo[6.4.0.0-[2,4]]dodeca-1(8),9,11-trien-5-yl]carbamate(151.0 mg, 0.50 mmol) was treated with 4N hydrogen chloride in dioxane(10 mL) for 1 hour at room temperature. The reaction mixture wasconcentrated under vacuum to provide the title compound (50 mg crude).LC-MS (Method C): m/z=203.1 [M+H]⁺, 1.043 min.

Step 4: Preparation of5-benzyl-N-((2S)-4-methyl-3-oxo-1,1a,2,3,4,8b-hexahydrobenzo[b]cyclopropa[d]azepin-2-yl)isoxazole-3-carboxamide

The crude product obtained using Amide Coupling Procedure C was purifiedby reverse phase chromatography using an Xbridge Phenyl OBD 5 μm, 19×150mm column; mobile phase, water (10 mmol/L NH₄HCO₃) and ACN (50.0% ACN to70.0% in 7 min) to afford the title compound. ¹H NMR (300 MHz, DMSO-d₆)δ 8.82 (d, J=7.5 Hz, 1H), 7.47 (d, J=7.5 Hz, 1H), 7.39-7.20 (m, 8H),6.60 (s, 1H), 4.45 (d, J=7.5 Hz, 1H), 4.22 (s, 2H), 3.22 (s, 3H),2.30-2.21 (m, 1H), 1.92-1.84 (m, 1H), 1.08-1.01 (m, 2H). LC-MS (MethodH): m/z=388.1 [M+H]⁺, 1.700 min.

This mixture was resolved by chiral HPLC on a Chiralpak IB (25×2.0 cm),5 m column using a mobile phase ofn-hexane/(ethanol/methanol/dichloromethane 45/45/10+0.1% isopropylamine)60/40% v/v with a flow rate of 18 mL/min to afford the two separatedenantiomers.

First eluting enantiomer (6.3 min), Enantiomer 1: ¹H NMR (400 MHz,CDCl₃) δ 8.13 (d, J=7.0 Hz, 1H), 7.40-7.16 (m, 8H), 7.10 (dd, J=7.8, 1.4Hz, 1H), 6.35 (s, 1H), 4.76 (d, J=7.2 Hz, 1H), 4.12 (s, 2H), 3.35 (s,3H), 2.17-2.08 (m, 1H), 2.02 (td, J=8.7, 4.9 Hz, 1H), 1.22 (q, J=5.3 Hz,1H), 1.05 (td, J=8.5, 6.5 Hz, 1H). LC-MS (Method A): m/z=388.3 [M+H]⁺,1.17 min. e.e.>99.9% as determined on a Chiralpak IB (25×0.46 cm), 5 μmcolumn using a mobile phase ofn-hexane/(ethanol/methanol/dichloromethane 45/45/10+0.1% isopropylamine)60/40% v/v with a flow rate of 1 mL/min.

Second eluting enantiomer (7.9 min), Enantiomer 2: ¹H NMR (400 MHz,CDCl₃) δ 8.14 (d, J=7.3 Hz, 1H), 7.41-7.17 (m, 8H), 7.12 (dd, J=7.7, 1.6Hz, 1H), 6.37 (s, 1H), 4.78 (d, J=7.0 Hz, 1H), 4.14 (s, 2H), 3.36 (s,3H), 2.14 (td, J=9.2, 5.4 Hz, 1H), 2.03 (td, J=8.7, 5.0 Hz, 1H), 1.23(q, J=5.3 Hz, 1H), 1.07 (td, J=8.5, 6.3 Hz, 1H). LC-MS (Method A):m/z=388.3 [M+H]⁺, 1.17 min. e.e.>99.9% as determined on a Chiralpak IB(25×0.46 cm), 5 μm column using a mobile phase ofn-hexane/(ethanol/methanol/dichloromethane 45/45/10+0.1% isopropylamine)60/40% v/v with a flow rate of 1 mL/min.

Example 8:(S)—N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-5-(1-phenylcyclopropyl)isoxazole-3-carboxamide

Step 1: Preparation of methyl5-(1-phenylcyclopropyl)-1,2-oxazole-3-carboxylate

A solution of 1-methyl-1-nitrosourea (449.8 mg, 4.36 mmol) in ether (10mL) was added dropwise to a solution of potassium hydroxide (359.1 mg,6.40 mmol) in water (0.54 mL) with stirring at 0° C. After stirring for0.5 hour at 0° C., the organic phase was separated to provide a solutionof diazomethane (10 mL). To a solution of ethyl5-(1-phenylethenyl)-1,2-oxazole-3-carboxylate (50.0 mg, 0.21 mmol) intetrahydrofuran (3 mL) was added the solution of diazomethane (10 mL)with stirring at 0° C. followed by the addition of a solution ofpalladium diacetate (4.7 mg, 0.02 mmol) in tetrahydrofuran (1 mL)dropwise with stirring at 0° C. The resulting solution was stirredovernight at room temperature. The solids were removed by filtration andthe filtrate was concentrated under vacuum. The residue was purified bycolumn chromatography (ethyl acetate/petroleum ether, 1/5) to afford thetitle compound (30 mg, 57%) as a yellow solid. LC-MS (Method C):m/z=244.0 [M+H]⁺, 1.519 min.

Step 2: Preparation of 5-(1-phenylcyclopropyl)-1,2-oxazole-3-carboxylicacid

A solution of methyl 5-(1-phenylcyclopropyl)-1,2-oxazole-3-carboxylate(25.0 mg, 0.10 mmol) and lithium hydroxide (4.8 mg, 0.20 mmol) inmethanol/water=3/1 (2 mL) was stirred for 2 hours at room temperature.The pH value of the solution was adjusted to 6-7 with 1N hydrochloricacid. The resulting solution was extracted with ethyl acetate (3×10 mL)and the combined organic layers were dried over anhydrous sodiumsulfate, filtered and concentrated under vacuum to afford the titlecompound (20 mg crude). LC-MS (Method G): m/z=230 [M+H]⁺, 0.700 min.

Step 3: Preparation of(S)—N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-5-(1-phenylcyclopropyl)isoxazole-3-carboxamide

The crude product obtained using Amide Coupling Procedure B was purifiedby reverse phase chromatography using an Xbridge Phenyl OBD 5 μm, 19×150mm column; mobile phase, water (10 mmol/L NH₄HCO₃) and ACN (50.0% ACN to70.0% in 7 min) to afford the title compound. ¹H NMR (300 MHz, DMSO-d₆)δ 8.82 (d, J=8.1 Hz, 1H), 7.52-7.48 (m, 1H), 7.38-7.25 (m, 7H),7.24-7.20 (m, 1H), 6.36 (s, 1H), 4.87-4.77 (m, 1H), 4.55 (dd, J=9.9,11.7 Hz, 1H), 4.38 (dd, J=8.1, 9.9 Hz, 1H), 3.30 (s, 3H), 1.57-1.52 (m,2H), 1.45-1.41 (m, 2H). LC-MS (Method H): m/z=404.2 [M+H]⁺, 1.766 min.

Example 9:(S)-5-benzyl-N-(1-methyl-2-oxo-1,2,3,4-tetrahydrospiro[benzo[b]azepine-5,1′-cyclopropan]-3-yl)isoxazole-3-carboxamide

Step 1: Preparation of tert-butylN-[(3S)-1-methyl-2-oxo-1,2,3,4-tetrahydrospiro[1-benzazepine-5,1-cyclopropane]-3-yl]carbamate

A solution of 1-methyl-1-nitrosourea (255.8 mg, 2.48 mmol) in ether (10mL) was added dropwise to a solution of potassium hydroxide (278 mg,4.96 mmol) in water (0.4 mL) with stirring at 0° C. After stirring for0.5 hour at 0° C., the organic phase was separated to provide a solutionof diazomethane (10 mL). To a solution of tert-butylN-[(3R)-1-methyl-2-oxo-2,3-dihydro-1H-1-benzazepin-3-yl]carbamate (75.0mg, 0.25 mmol) in tetrahydrofuran (1.5 mL) was added the solution ofdiazomethane (10 mL) dropwise followed by the addition of a solution ofpalladium diacetate (5.5 mg, 0.02 mmol) in tetrahydrofuran (0.5 mL)dropwise with stirring at 0° C. The resulting solution was stirredovernight at room temperature. The solids were removed by filtration andthe filtrate was concentrated under vacuum. The residue was purified bycolumn chromatography (ethyl acetate/petroleum ether, 1/5) to afford thetitle compound (55 mg, 70%). LC-MS (Method C): m/z=317.2 [M+H]⁺, 1.531min.

Step 2: Preparation of(3S)-3-amino-1-methyl-1,2,3,4-tetrahydrospiro[1-benzazepine-5,1-cyclopropane]-2-onehydrochloride

tert-ButylN-[(3S)-1-methyl-2-oxo-1,2,3,4-tetrahydrospiro[1-benzazepine-5,1-cyclopropane]-3-yl]carbamate(40.0 mg, 0.13 mmol) was treated with 4N hydrogen chloride in dioxane (6mL) for 1 hour at room temperature. The resulting mixture wasconcentrated under vacuum to afford the title compound (25.2 mg) as ayellow solid. LC-MS (Method K): m/z=217.2 [M+H]⁺, 0.635 min.

Step 3: Preparation of(S)-5-benzyl-N-(1-methyl-2-oxo-1,2,3,4-tetrahydrospiro[benzo[b]azepine-5,1′-cyclopropan]-3-yl)isoxazole-3-carboxamide

The crude product obtained using Amide Coupling Procedure C was purifiedby reverse phase chromatography using an Xbridge Phenyl OBD 5 μm, 19×150mm column; mobile phase, water (10 mmol/L NH₄HCO₃) and ACN (50% to 70%in 7 min) to afford the title compound (17.8 mg, 44%) as a white solid.This compound was further purified by chiral HPLC on a Chiralpak AS-H(25×2.0 cm), 5 m column using a mobile phase ofn-hexane/(2-propanol/MeOH 1/1+0.1% isopropylamine) 60/40% v/v to affordthe title compound. ¹H NMR (400 MHz, CDCl₃) δ 7.78 (d, J=7.0 Hz, 1H),7.39-7.19 (m, 9H), 6.31 (s, 1H), 4.69 (td, J=7.6, 10.9 Hz, 1H), 4.11 (s,2H), 3.43 (s, 3H), 3.13 (dd, J=12.3, 8.3 Hz, 1H), 1.33 (dd, J=12.5, 11.0Hz, 1H), 1.16-1.08 (m, 1H), 0.88 (ddd, J=9.3, 5.5, 4.3 Hz, 1H), 0.71(td, J=5.5, 9.3 Hz, 1H), 0.51-0.42 (m, 1H). LC-MS (Method A): m/z=402.2[M+H]⁺, 1.21 min. e.e.>99.5% as determined on a Chiralpak AS-H (25×0.46cm), 5 m column using a mobile phase of n-hexane/(2-propanol/MeOH1/1+0.1% isopropylamine) 60/40% v/v.

Example 10:5-benzyl-N-(5,5-difluoro-1-methyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-3-yl)-4H-1,2,4-triazole-3-carboxamide

Step 1: Preparation of tert-butyl(5,5-difluoro-1-methyl-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepin-3-yl)carbamate

A solution of tert-butyl(1-methyl-2,5-dioxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-3-yl)carbamate(200 mg, 0.658 mmol) in bis(2-methoxyethyl)aminosulfur trifluoride (6mL) was heated to 65° C. and stirred overnight. The reaction mixture wasallowed to cool to ambient temperature, quenched with water (30 mL) andextracted with ethyl acetate (3×40 mL). The combined organic layers werewashed with saturated aqueous sodium carbonate and brine, dried overanhydrous sodium sulfate and concentrated under vacuum. The residue waspurified by column chromatography (ethyl acetate/hexane, 1/20) to affordthe title compound (60 mg, 30%). LC-MS (Method E): m/z=327 [M+H]⁺, 1.035min.

Step 2: Preparation of3-amino-5,5-difluoro-1-methyl-4,5-dihydro-1H-benzo[b]azepin-2(3H)-one

tert-Butyl(5,5-difluoro-1-methyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-3-yl)carbamate(40 mg, 0.184 mmol) was added to a solution of (4N) hydrogen chloride in1,4-dioxane (30 mL). The resulting solution was stirred for 2 hours atambient temperature and concentrated under vacuum to afford the titlecompound (50 mg crude) as a yellow solid. LC-MS (Method N): m/z=227[M+H]⁺, 0.995 min.

Step 3: Preparation of5-benzyl-N-(5,5-difluoro-1-methyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-3-yl)-4H-1,2,4-triazole-3-carboxamide

The crude product obtained using Amide Coupling Procedure C was purifiedby reverse phase chromatography using an Xbridge Prep C18 5 μm, 19×150mm column; Mobile phase: Phase A: aqueous ammonium bicarbonate (0.05%);Phase B: acetonitrile; (20% to 80% in 12 min) to afford the titlecompound. ¹H NMR (400 MHz, DMSO-d₆) δ 14.25 (s, 1H), 8.59 (s, 1H), 7.63(m 3H), 7.44 (t, J=7.5 Hz, 1H), 7.35-7.18 (m, 5H), 4.52 (dt, J=11.8, 7.8Hz, 1H), 4.10 (s, 2H), 3.26 (s, 3H), 3.15-2.81 (m, 2H). LC-MS (MethodL): m/z=412.1 [M+H]⁺, 1.309 min.

Example 11 and 12:5-benzyl-N-((3S,5R)-5-fluoro-1-methyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-3-yl)-4H-1,2,4-triazole-3-carboxamideand5-benzyl-N-((3R,5S)-5-fluoro-1-methyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-3-yl)-4H-1,2,4-triazole-3-carboxamide(Example 11) and5-benzyl-N-((3S,5S)-5-fluoro-1-methyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-3-yl)-4H-1,2,4-triazole-3-carboxamideand5-benzyl-N-((3R,5R)-5-fluoro-1-methyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-3-yl)-4H-1,2,4-triazole-3-carboxamide(Example 12)

The crude product obtained using Amide Coupling Procedure A was purifiedby reverse phase column chromatography using an Xbridge Phenyl OBD 5 μm,19×150 mm column; mobile phase, water (10 mmol/L NH₄HCO₃) and ACN (25.0%to 55.0% in 7 min) to afford the title compounds:

Example 11, first eluting isomer: ¹H NMR (400 MHz, DMSO-d₆) δ 14.41 (s,1H), 8.41 (s, 1H), 7.65-7.49 (m, 2H), 7.45 (dt, J=7.7, 1.7 Hz, 1H),7.40-7.20 (m, 6H), 5.76 (dd, J=47.0, 4.8 Hz, 1H), 4.47 (dt, J=11.4, 7.5Hz, 1H), 4.12 (s, 2H), 3.27 (s, 3H), 2.94-2.56 (m, 2H). LC-MS (MethodF): m/z=394.1 [M+H]⁺, 1.085 min.

Example 12, second eluting isomer: ¹H NMR (400 MHz, DMSO-d₆) δ 14.37 (s,1H), 8.41 (s, 1H), 7.58-7.38 (m, 4H), 7.38-7.20 (m, 5H), 5.92 (ddd,J=46.6, 10.5, 8.1 Hz, 1H), 4.30 (dt, J=11.4, 7.9 Hz, 1H), 4.12 (s, 2H),3.31 (s, 3H), 2.96-2.78 (m, 1H), 2.41-2.30 (m, 1H). LC-MS (Method F):m/z=394.1 [M+H]⁺, 1.156 min.

Example 11: Chiral Separation

This mixture was resolved by chiral HPLC on a Whelk O-1 (R,R) (25×2.0cm), 10 m column using a mobile phase of n-hexane/(ethanol+0.1%isopropylamine) 30/70% v/v with a flow rate of 18 mL/min to afford thetwo separated enantiomers.

First eluting enantiomer (6.8 min), Enantiomer 1: ¹H NMR (400 MHz,CDCl₃) δ 8.27 (d, J=6.8 Hz, 1H), 7.35 (m, 9H), 5.51 (m, 1H), 4.74 (dt,J=11.0, 7.1 Hz, 1H), 4.15 (s, 2H), 3.41 (s, 3H), 3.07 (m, 1H), 2.44 (m,1H). LC-MS (Method A): m/z=394.3 [M+H]⁺, 0.87 min. e.e.>99.9% asdetermined on a Whelk O-1 (R,R) (25×0.46 cm), 5 μm column using a mobilephase of n-hexane/(ethanol+0.1% isopropylamine) 30/70% v/v with a flowrate of 1 mL/min.

Second eluting enantiomer (8.9 min), Enantiomer 2: ¹H NMR (400 MHz,CDCl₃) δ 8.27 (d, J=6.8 Hz, 1H), 7.35 (m, 9H), 5.51 (m, 1H), 4.74 (dt,J=11.0, 7.1 Hz, 1H), 4.15 (s, 2H), 3.41 (s, 3H), 3.07 (m, 1H), 2.44 (m,1H). LC-MS (Method A): m/z=394.3 [M+H]⁺, 0.86 min. e.e.>99.9% asdetermined on a Whelk O-1 (R,R) (25×0.46 cm), 5 μm column using a mobilephase of n-hexane/(ethanol+0.1% isopropylamine) 30/70% v/v with a flowrate of 1 mL/min.

Example 12: Chiral Separation

This mixture was resolved by chiral HPLC on a Chiralcel OJ-H (25×2.0cm), 5 m column using a mobile phase of n-hexane/(ethanol/methanol1/1+0.1% isopropylamine) 30/70% v/v with a flow rate of 18 mL/min toafford the two separated enantiomers.

First eluting enantiomer (4.8 min), Enantiomer 1: ¹H NMR (400 MHz,CDCl₃) δ 8.14 (d, J=6.1 Hz, 1H), 7.62-7.14 (m, 9H), 5.87-5.64 (m, 1H),4.67-4.54 (m, 1H), 4.17 (s, 2H), 3.44 (s, 3H), 3.03-2.85 (m, 1H),2.66-2.53 (m, 1H). LC-MS (Method U): m/z=394.2 [M+H]⁺, 0.75 min.e.e.>99.9% as determined on a Chiralcel OJ-H (25×0.46 cm), 5 μm columnusing a mobile phase of n-hexane/(ethanol/methanol 1/1+0.1%isopropylamine) 50/50% v/v with a flow rate of 1 mL/min.

Second eluting enantiomer (7.0 min), Enantiomer 2: ¹H NMR (400 MHz,CDCl₃) δ 8.14 (d, J=6.3 Hz, 1H), 7.62-7.15 (m, 10H), 5.86-5.63 (m, 1H),4.66-4.53 (m, 1H), 4.12 (s, 2H), 3.42 (s, 3H), 3.00-2.82 (m, 1H),2.64-2.52 (m, 1H). LC-MS (Method U): m/z=394.2 [M+H]⁺, 0.74 min.e.e.>99.9% as determined on a Chiralcel OJ-H (25×0.46 cm), 5 μm columnusing a mobile phase of n-hexane/(ethanol/methanol 1/1+0.1%isopropylamine) 50/50% v/v with a flow rate of 1 mL/min.

Example 13:(R)—N—((S)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4-phenyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole-2-carboxamide

Step 1: Preparation of(2S,3R)-1-nitroso-3-phenylpyrrolidine-2-carboxylic acid

(2S,3R)-3-phenylpyrrolidine-2-carboxylic acid (1.01 g, 5.23 mmol) wasadded to a solution of sodium nitrite (800 mg, 11.59 mmol) in water (5mL). Concentrated hydrochloric acid (5 mL) was added at 0° C. Thereaction mixture was stirred overnight at room temperature, diluted withwater (50 mL) and extracted with ethyl acetate (3×50 mL). The combinedorganic phases were dried over sodium sulfate, filtered and concentratedunder reduced pressure to afford the title compound (700 mg crude).LC-MS (Method I): m/z=220.95[M+H]⁺, 0.741 min.

Step 2: Preparation of(R)-3-oxo-4-phenyl-3,4,5,6-tetrahydropyrrolo[1,2c][1,2,3]oxadiazol-7-ium-3a-ide

To a solution of (2S,3R)-1-nitroso-3-phenylpyrrolidine-2-carboxylic acid(700 mg, 3.18 mmol) in ether (7 mL) at 0° C. was added trifluoroaceticanhydride (1.01 g, 4.76 mmol) dropwise. The resulting solution wasstirred for 2 hours at room temperature. The reaction mixture wasconcentrated under vacuum and diluted with water (50 mL). The pH valueof the solution was adjusted to 8 with potassium carbonate (0.5 M). Theresulting solution was extracted with dichloromethane (3×50 mL). Thecombined organic layers were dried over sodium sulfate, filtered andconcentrated under vacuum. The residue was purified by columnchromatography (ethyl acetate/petroleum ether, 1:1) to afford the titlecompound (380 mg, 59%) d. LC-MS (Method I): m/z=202.9 [M+H]⁺, 0.725 min.

Step 3: Preparation of ethyl(4R)-4-phenyl-4H,5H,6H-pyrrolo[1,2-b]pyrazole-3-carboxylate

To a solution of(R)-3-oxo-4-phenyl-3,4,5,6-tetrahydropyrrolo[1,2-c][1,2,3]oxadiazol-7-ium-3a-ide(380 mg, 1.88 mmol) in o-xylene (6 mL), purged and maintained with aninert atmosphere of nitrogen, was added ethyl prop-2-ynoate (240 mg,2.45 mmol) dropwise. The resulting solution was stirred overnight at125° C. in an oil bath. The resulting mixture was concentrated undervacuum. The residue was purified by column chromatography (ethylacetate/petroleum ether, 1:1) to afford the title compound (100 mg,21%). LC-MS (Method J): m/z=257.1 [M+H]⁺, 1.367 min.

Step 4: Preparation of(4R)-4-phenyl-4H,5H,6H-pyrrolo[1,2-b]pyrazole-2-carboxylic acid

To a solution of ethyl(4R)-4-phenyl-4H,5H,6H-pyrrolo[1,2-b]pyrazole-2-carboxylate (100 mg,0.39 mmol) in methanol (2.1 mL) and water (0.7 mL) was added potassiumhydroxide (67 mg, 1.19 mmol). The resulting solution was stirredovernight at room temperature, concentrated under vacuum and theresulting residue was diluted with water. The pH value of the solutionwas adjusted to 3 with 3N hydrochloric acid. The resulting solid wascollected by filtration to afford the title compound (80 mg, 90%). LC-MS(Method I): m/z=228.9 [M+H]⁺, 0.804 min.

Step 5: Preparation of(R)—N—((S)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4-phenyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole-2-carboxamide

The crude product obtained using Amide Coupling Procedure B was purifiedby reverse phase chromatography using an Xbridge Phenyl OBD 5 μm, 19×150mm column; mobile phase, water (10 mmol/L NH₄HCO₃) and ACN (25.0% to55.0% in 7 min) to afford the title compound. ¹H-NMR (400 MHz, DMSO-d₆)δ 8.12 (d, J=8.1 Hz, 1H), 7.51 (dd, J=7.5, 1.9 Hz, 1H), 7.39-7.20 (m,8H), 6.32 (d, J=0.9 Hz, 1H), 4.84 (dt, J=11.5, 7.9 Hz, 1H), 4.61-4.48(m, 2H), 4.45-4.31 (m, 2H), 4.22 (dt, J=11.0, 7.7 Hz, 1H), 3.32 (s, 3H),3.09 (dtd, J=12.7, 8.3, 4.2 Hz, 1H), 2.51-2.41 (m, 1H). LC-MS (MethodJ): m/z=403.2 [M+H]⁺, 1.499 min.

Example 14:(S)—N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-5-(2,2,2-trifluoroethyl)isoxazole-3-carboxamide

Step 1: Preparation of methyl 5-(bromomethyl)isoxazole-3-carboxylate

To a solution of methyl 5-methylisoxazole-3-carboxylate (4.65 g, 30mmol) and N-bromosuccinimide in carbon tetrachloride (250 mL) was addedbenzoyl peroxide (2 mg, 0.1 mol %). The resulting mixture was refluxedat 80° C. for 24 hours. The solids were removed by filtration and thefiltrate was concentrated under vacuum. The residue was purified bycolumn chromatography (ethyl acetate/hexane, 1/5) to afford the titlecompound (1.6 g, 23%) as a white solid. LC-MS (Method C): m/z=221.7[M+H]⁺, 0.746 min.

Step 2: Preparation of methyl5-(2,2,2-trifluoroethyl)isoxazole-3-carboxylate

To a mixture of methyl 5-(bromomethyl)isoxazole-3-carboxylate (350 mg,1.59 mmol) and cuprous iodide (570 mg, 3.00 mmol) inN,N-dimethylformamide (10 mL) was added methyl2,2-difluoro-2-(fluorosulfonyl)acetate (1.44 g, 7.50 mmol). Theresulting mixture was heated at 100° C. for 20 hours. After cooling toroom temperature, the reaction mixture was diluted with water (25 mL)and extracted with ethyl acetate (3×25 mL). The combined organic phaseswere dried over sodium sulfate, filtered and concentrated under reducedpressure. The residue was purified by column chromatography (ethylacetate/hexane, 1/5) to afford the title compound (125 mg, 37%) as ayellow solid. LC-MS (Method C): m/z=209.9 [M+H]⁺, 0.788 min.

Step 3: Preparation of 5-(2,2,2-trifluoroethyl)isoxazole-3-carboxylicacid

To a solution of methyl 5-(2,2,2-trifluoroethyl)isoxazole-3-carboxylate(90 mg, 0.43 mmol) in 4:1 THF:H₂O (2.5 mL) was added lithium hydroxide(72 mg, 3 mmol). The resulting solution was stirred for 40 min at roomtemperature. After completion of the reaction the solvent was evaporatedunder reduced pressure and to the resulting residue was added water (25mL). This solution was washed with ethyl acetate (3×50 mL). The aqueouslayer was acidified with 1N hydrochloric acid to pH-3-4, and extractedwith ethyl acetate (3×20 mL). The combined organic phases from thisextraction were dried over sodium sulfate, filtered and concentratedunder reduced pressure to afford the title compound (43 mg crude), whichwas used directly for the next step without further purification. LC-MS(Method D): m/z=196.9 [M+H]⁺, 0.290 min.

Step 4: Preparation of(S)—N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-5-(2,2,2-trifluoroethyl)isoxazole-3-carboxamide

The crude product obtained using Amide Coupling Procedure C was purifiedby crystallization (ethanol/n-hexane) to afford the title compound. ¹HNMR (300 MHz, Chloroform-d) δ 7.80 (d, J=7.0 Hz, 1H), 7.26-7.19 (m, 4H),6.71 (s, 1H), 5.04 (dt, J=11.1, 7.1 Hz, 1H), 4.76 (dd, J=9.8, 7.4 Hz,1H), 4.28 (dd, J=11.1, 9.7 Hz, 1H), 3.69 (q, J=9.7 Hz, 2H), 3.46 (s,3H). LC-MS (Method E): m/z=370.2 [M+H]⁺, 2.462 min.

Example 15:5-benzyl-N-(6,7,8,9-tetrahydro-5H-benzo[7]annulen-7-yl)isoxazole-3-carboxamide

The crude product obtained using Amide Coupling Procedure C was purifiedby Prep-HPLC with the following conditions: Column, Xbridge Phenyl OBDColumn, 5 μm, 19×150 mm; mobile phase, water (10 mmol/L NH₄HCO₃) and ACN(50.0% ACN to 70.0% over 7 min); Detector, UV 254 & 220 nm to afford thetitle compound. ¹H NMR (300 MHz, DMSO-d₆) δ 8.63 (d, J=8.4 Hz, 1H),7.25-7.14 (m, 5H), 7.15-7.07 (m, 4H), 6.52 (s, 1H), 4.19 (s, 2H),4.17-4.04 (m, 1H), 2.89-2.69 (m, 4H), 2.02-1.97 (m, 2H), 1.43-1.23 (m,2H). LC-MS (Method F): m/z=347.1 [M+H]⁺, 1.652 min.

Example 16:(S)-1-benzyl-3-methyl-N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-pyrazole-5-carboxamide

Step 1: Preparation of ethyl 1-benzyl-3-methyl-1H-pyrazole-5-carboxylate

To a solution of ethyl 2,4-dioxopentanoate (0.5 g, 3.20 mmol) andbenzylhydrazine hydrochloride (0.75 g, 3.84 mmol) in ethanol (10 mL) wasadded N,N-diisopropylethylamine (1.2 g, 9.60 mmol). After stirringovernight at room temperature, the reaction mixture was diluted withwater (20 mL) and extracted with ethyl acetate (3×50 mL). The combinedorganic layers were washed with brine, dried over anhydrous sodiumsulfate, filtered and concentrated under reduced pressure. The residuewas purified by column chromatography (ethyl acetate/petroleum ether,1/1) to afford the title compound (0.5 g, 65%) as a yellow oil. LC-MS(Method S): m/z=245.2 [M+H]⁺, 1.070 min.

Step 2: Preparation of 1-benzyl-3-methyl-1H-pyrazole-5-carboxylic acid

A solution of sodium hydroxide (0.25 g, 6.02 mmol) in water (1 mL) wasadded to a stirred solution of ethyl1-benzyl-3-methyl-1H-pyrazole-5-carboxylate (0.5 g, 2.01 mmol) inethanol (2 mL). The resulting mixture was stirred overnight at 80° C.After cooling to room temperature, the reaction mixture was adjusted topH=3-4 with aqueous hydrochloric acid (1 N, 20 mL) and extracted withethyl acetate (3×50 mL). The combined organic layers were washed withbrine, dried over anhydrous sodium sulfate, filtered and concentratedunder reduced pressure to afford the title compound (0.4 g, 90%) as awhite solid, which was used directly in the next step without furtherpurification. LC-MS (Method C): m/z=217.2 [M+H]⁺, 1.219 min.

Step 3: Preparation of(S)-1-benzyl-3-methyl-N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-pyrazole-5-carboxamide

The crude product obtained using Amide Coupling Procedure C was purifiedby Prep-HPLC with the following conditions: Column, Xbridge Phenyl OBDColumn, 5 μm, 19×150 mm; mobile phase, water (10 mmol/L NH₄HCO₃) and ACN(50.0% ACN to 70.0% over 7 min); Detector, UV 254 & 220 nm to afford thetitle compound. ¹H NMR (400 MHz, DMSO-d₆) δ 8.68 (d, J=8.4 Hz, 1H),7.53-7.47 (m, 1H), 7.35-7.19 (m, 6H), 7.11-7.07 (m, 2H), 6.82 (s, 1H),5.64-5.51 (m, 2H), 4.88-4.81 (m, 1H), 4.55-4.49 (m, 1H), 4.40-4.35 (m,1H), 3.30 (s, 3H), 2.20 (s, 3H). LC-MS (Method L): m/z=391.1 [M+H]⁺,1.437 min.

Example 17:(R)—N—((S)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4-phenyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole-3-carboxamide

Step 1: Preparation of ethyl(4R)-4-phenyl-4H,5H,6H-pyrrolo[1,2-b]pyrazole-3-carboxylate

To a stirring solution of(R)-3-oxo-4-phenyl-3,4,5,6-tetrahydropyrrolo[1,2-c][1,2,3]oxadiazol-7-ium-3a-ide(380 mg, 1.88 mmol) in o-xylene (6 mL) under nitrogen atmosphere wasadded ethyl prop-2-ynoate (240 mg, 2.45 mmol). The resulting mixture washeated to 125° C. and stirred overnight in an oil bath. The reactionmixture was cooled to rt, concentrated under reduced pressure and theresulting residue was purified by column chromatography (ethylacetate/petroleum ether, 1/1) to afford the title compound (120 mg, 25%)as a light yellow oil. LC-MS (Method J): m/z=257.0 [M+H]⁺, 1.323 min.

Step 2: Preparation of(4R)-4-phenyl-4H,5H,6H-pyrrolo[1,2-b]pyrazole-3-carboxylic acid

A solution of potassium hydroxide (67 mg, 1.19 mmol) in water (7 mL) wasadded to a solution of ethyl(4R)-4-phenyl-4H,5H,6H-pyrrolo[1,2-b]pyrazole-3-carboxylate (100 mg,0.39 mmol) in methanol (2.1 mL). After stirring overnight at roomtemperature, the reaction mixture was concentrated under reducedpressure and diluted with water. The pH value of the solution wasadjusted to 3 with hydrochloric acid (3 N, 20 mL). The precipitate wascollected by filtration to afford the title compound (50 mg, 47%) as ayellow solid. LC-MS (Method I): m/z=228.9 [M+H]⁺, 0.738 min.

Step 3: Preparation of(R)—N—((S)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4-phenyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole-3-carboxamide

The crude product obtained using Amide Coupling Procedure B was purifiedby preparative HPLC with the following conditions: Column, XbridgePhenyl OBD Column, 5 μm, 19×150 mm; mobile phase, water (10 mmol/LNH₄HCO₃) and ACN (25.0% ACN to 55.0% over 7 min); Detector, UV 254 & 220nm to afford the title compound. ¹H NMR (400 MHz, DMSO-d₆) δ 8.02 (s,1H), 7.79 (d, J=8.8 Hz, 1H), 7.44 (dd, J=7.6, 2.0 Hz, 1H), 7.34-7.14 (m,6H), 7.10-7.02 (m, 2H), 4.77-4.58 (m, 2H), 4.35-4.23 (m, 1H), 4.22-4.03(m, 3H), 3.26 (s, 3H), 3.19-3.05 (m, 1H), 2.39 (dq, J=8.8, 4.3 Hz, 1H).LC-MS (Method O): m/z=403.0 [M+H]⁺, 1.334 min.

Example 18:(S)—N-benzyl-2-((5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)amino)acetamide

A mixture of(3S)-3-amino-5-methyl-2,3,4,5-tetrahydro-1,5-benzoxazepin-4-onehydrochloride (40 mg, 0.175 mmol, e.e.=90%), N-benzyl-2-chloroacetamide(18 mg, 0.097 mmol), K₂CO₃ (27 mg, 0.195 mmol), and KI (32 mg, 0.195mmol) in DMF (3 mL) was stirred at 30° C. for 16 h. The mixture wasdiluted with EtOAc and washed twice with sat. NH₄Cl solution. Theaqueous portion was extracted with EtOAc. The combined organic portionswere dried over Na₂SO₄, filtered and concentrated under reducedpressure. The crude product was purified by column chromatography(cyclohexane-EtOAc, 80:20 to 0:100) to afford the title compound. ¹H NMR(400 MHz, CDCl₃) δ 7.46-7.08 (m, 10H), 4.51-4.37 (m, 2H), 4.33 (dd,J=10.2, 7.4 Hz, 1H), 4.12 (t, J=10.8 Hz, 1H), 3.61-3.43 (m, 3H), 3.41(s, 3H), 3.06-2.97 (m, 1H). LC-MS (Method A): m/z=340.0 [M+H]⁺, 0.70min. e.e. =88% as determined on a Chiralcel OD-H (25×0.46 cm), 5 μmcolumn using a mobile phase of n-hexane/(ethanol+0.1% isopropylamine)35/65% v/v.

Example 19:(S)-5-benzyl-N-(5-ethyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)isoxazole-3-carboxamide

Step 1: Preparation of tert-butylN-((3S)-5-ethyl-4-oxo-2,3,4,5-tetrahydro-1,5-benzoxazepin-3-yl)carbamate

Sodium hydride (8.64 mg, 0.22 mmol) was added to a stirring solution oftert-butylN-((3S)-4-oxo-2,3,4,5-tetrahydro-1,5-benzoxazepin-3-yl)carbamate (50 mg,0.18 mmol) in N,N-dimethylformamide (5 mL). The resulting mixture wasstirred for 1 hour at room temperature. Iodoethane (33.7 mg, 0.21 mmol)was added dropwise. After stirring for 3 hours at room temperature, thereaction mixture was quenched with water (10 mL) and extracted withethyl acetate (3×10 mL). The combined organic layers were washed withbrine, dried over anhydrous sodium sulfate, filtered and concentratedunder reduced pressure. The resulting residue was purified by columnchromatography (ethyl acetate/petroleum ether, 1/3) to afford the titlecompound (40 mg, 73%) as a yellow solid. LC-MS (Method S): m/z=307.2[M+H]⁺, 1.021 min.

Step 2: Preparation of(3S)-3-amino-5-ethyl-2,3,4,5-tetrahydro-1,5-benzoxazepin-4-onehydrochloride

tert-ButylN-((3S)-5-ethyl-4-oxo-2,3,4,5-tetrahydro-1,5-benzoxazepin-3-yl)carbamate(40 mg, 0.13 mmol) was added to a solution of hydrogen chloride indioxane (4 M, 10 mL). The reaction mixture was stirred for 3 hours atroom temperature and concentrated under reduced pressure to afford thetitle compound (30 mg) as a white solid, which was used directly in thenext step without further purification. LC-MS (Method D): m/z=207.1[M+H]⁺, 0.930 min.

Step 3: Preparation of(S)-5-benzyl-N-(5-ethyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)isoxazole-3-carboxamide

The crude product obtained using Amide Coupling Procedure B was purifiedby Prep-HPLC with the following conditions: Column, XBridge Prep C18 OBDColumn, 5 μm, 19×150 mm; mobile phase, water (0.05% TFA) and ACN (45.0%ACN to 70.0% over 7 min); Detector, UV 254 & 220 nm to afford the titlecompounds. ¹H NMR (300 MHz, DMSO-d₆) δ 8.82 (d, J=7.8 Hz, 1H), 7.54-7.51(m, 1H), 7.38-7.21 (m, 8H), 6.54 (s, 1H), 4.84-4.75 (m, 1H), 4.56 (t,J=11.4 Hz, 1H), 4.39-4.33 (m, 1H), 4.21 (s, 2H), 4.10-4.03 (m, 1H),3.67-3.60 (m, 1H), 1.02 (t, J=7.2 Hz, 3H). LC-MS (Method D): m/z=392.2[M+H]⁺, 2.181 min.

Example 20:5-benzyl-N-(1-methyl-2,3,4,5-tetrahydro-1H-benzo[b]azepin-3-yl)-4H-1,2,4-triazole-3-carboxamide

Borane tetrahydrofuran complex (1M solution in THF, 570 μL, 0.570 mmol)was added dropwise to a solution of3-amino-1-methyl-2,3,4,5-tetrahydro-1H-1-benzazepin-2-one (50 mg, 0.26mmol) in THF (1 mL) which had been pre-cooled to 0° C. The reaction wasallowed to gradually warm to room temperature and stirred for 18 hbefore being quenched with 1M HC solution. The resulting mixture wasstirred at room temperature for 3 h. Volatiles were removed underreduced pressure. The crude product was purified by ion exchangechromatography on an SCX cartridge (MeOH then 7M NH₃ in MeOH) to affordthe title compound. ¹H NMR (400 MHz, DMSO-d₆) δ 7.14-7.02 (m, 2H),6.93-6.85 (m, 1H), 6.84-6.74 (m, 1H), 3.10-2.85 (m, 2H), 2.84-2.68 (m,4H), 2.66-2.54 (m, 1H), 2.48-2.36 (m, 1H), 1.89-1.77 (m, 1H), 1.75-1.55(m, 2H), 1.33-1.06 (m, 1H). LC-MS (Method A): m/z=177.2 [M+H]⁺, 0.40min.

The crude product obtained using Amide Coupling Procedure C was purifiedby column chromatography (CH₂Cl₂-MeOH, 95:5 to 80:20) and then byreverse phase chromatography (water-CH₃CN, 100:0 to 50:50) to afford thetitle compound as a mixture of enantiomers. ¹H NMR (400 MHz, DMSO-d₆) δ14.61-14.37 (m, 1H), 8.37-8.25 (m, 1H), 7.35-7.10 (m, 7H), 6.99-6.93 (m,1H), 6.85 (td, J=7.3, 1.1 Hz, 1H), 4.19-4.11 (m, 1H), 4.08 (s, 2H),3.05-2.98 (m, 1H), 2.84 (s, 3H), 2.81-2.73 (m, 2H), 2.65-2.58 (m, 1H),1.89-1.78 (m, 1H), 1.68-1.55 (m, 1H). LC-MS (Method A): m/z=362.4[M+H]⁺, 1.02 min.

Example 21:5-benzyl-N-((4S,9aR)-5-oxohexahydro-1H,3H-pyrrolo[2,1-c][1,4]oxazepin-4-yl)isoxazole-3-carboxamide

Example22:5-benzyl-N-((4S,9aS)-5-oxohexahydro-1H,3H-pyrrolo[2,1-c][1,4]oxazepin-4-yl)isoxazole-3-carboxamide

Example 23:(S)-5-benzyl-N-(1-methyl-2-oxoazepan-3-yl)-4H-1,2,4-triazole-3-carboxamide

The crude product obtained using Amide Coupling Procedure C was purifiedby column chromatography (CH₂Cl₂/MeOH 9:1), then by columnchromatography on KP-NH modified silica gel (EtOAc/MeOH 9:1) and then byreverse phase chromatography (water-CH₃CN, 70:30) to afford the titlecompound. ¹H NMR (400 MHz, DMSO-d₆) δ 14.44 (s, 1H), 8.34 (d, J=6.2 Hz,1H), 7.37-7.20 (m, 5H), 4.75-4.65 (m, 1H), 4.11 (s, 2H), 3.68 (dd,J=15.4, 11.4 Hz, 1H), 3.23 (dd, J=15.3, 5.2 Hz, 1H), 2.94 (s, 3H),2.01-1.93 (m, 1H), 1.92-1.82 (m, 1H), 1.81-1.67 (m, 2H), 1.45-1.28 (m,2H). LC-MS (Method A): m/z=328.3 [M+H]⁺, 0.74 min.

Example 24:(S)-5-cyano-1-methyl-N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-pyrrole-2-carboxamide

The crude product obtained using Amide Coupling Procedure C was purifiedby column chromatography (cyclohexane-EtOAc, 100:0 to 70:30) to affordthe title compound. ¹H NMR (400 MHz, CDCl₃) δ 7.32-7.19 (m, 4H), 7.11(d, J=6.6 Hz, 1H), 6.77 (d, J=4.3 Hz, 1H), 6.69 (d, J=4.3 Hz, 1H), 5.00(dt, J=11.2, 6.9 Hz, 1H), 4.77 (dd, J=9.7, 7.4 Hz, 1H), 4.25 (dd,J=11.1, 9.7 Hz, 1H), 4.00 (s, 3H), 3.47 (s, 3H). LC-MS (Method A):m/z=325.0 [M+H]⁺, 0.93 min.

Example 25:(S)-5-methyl-N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4H-1,2,4-triazole-3-carboxamide

The crude product obtained using Amide Coupling Procedure C was purifiedby Prep-HPLC with the following conditions: Column, Xbridge Phenyl OBDColumn, 5 μm, 19×150 mm; mobile phase, water (10 mmol/L NH₄HCO₃) and ACN(50.0% ACN to 70.0% over 7 min); Detector, UV 254 & 220 nm to afford thetitle compound. ¹H NMR (400 MHz, DMSO-d₆) δ 14.2 (br. s, 1H), 8.43 (d,J=6.8 Hz, 1H), 7.54-7.45 (m, 1H), 7.22-7.18 (m, 3H), 4.90-4.75 (m, 1H),4.58 (t, J=10.0 Hz, 1H), 4.47-4.35 (m, 1H), 4.39 (s, 3H), 2.39 (s, 3H).LC-MS (Method L): m/z=302.0 [M+H]⁺, 0.885 min.

Example 26:(S)—N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)acetamide

Acetic anhydride (20.5 mg, 0.20 mmol) was added to a solution of(3S)-3-amino-5-methyl-2,3,4,5-tetrahydro-1,5-benzoxazepin-4-onehydrochloride (45.6 mg, 0.20 mmol) and triethylamine (40 mg, 0.40 mmol)in dichloromethane (5 mL). After stirring at room temperature for 2hours, the reaction mixture was diluted with water (5 mL), and extractedwith dichloromethane (3×10 mL). The combined organic layers were washedwith brine, dried over anhydrous sodium sulfate, filtered andconcentrated under reduced pressure. The residue was purified byPrep-HPLC with the following conditions: Column, Xbridge Phenyl OBDColumn, 5 μm, 19×150 mm; mobile phase, water (10 mmol/L NH₄HCO₃) and ACN(50.0% ACN to 70.0% over 7 min); Detector, UV 254 & 220 nm to afford thetitle compound. ¹H NMR (400 MHz, DMSO-d₆) δ 8.25 (d, J=8.4 Hz, 1H),7.50-7.45 (m, 1H), 7.36-7.15 (m, 3H), 4.76-4.65 (m, 1H), 4.38-4.15 (m,2H), 3.29 (s, 3H), 1.84 (s, 3H). LC-MS (Method D): m/z=235.1 [M+H]⁺,1.340 min.

Example27:5-benzyl-N-((4S,9aS)-5-oxohexahydro-1H,3H-pyrrolo[2,1-c][1,4]oxazepin-4-yl)-4H-1,2,4-triazole-3-carboxamide

Step 1: Preparation of tert-butyl(2S)-2-{[(2S)-2-{[(benzyloxy)carbonyl]amino}-3-methoxy-3-oxopropoxy]methyl}pyrrolidine-1-carboxylate

Boron trifluoride diethyl etherate (0.52 mL, 4.25 mmol) was added to asolution of 1-benzyl 2-methyl (2S)-aziridine-1,2-dicarboxylate (2.00 g,8.50 mmol) and N-Boc-L-prolinol (6.85 g, 34.03 mmol) in dry CHCl₃ (20mL) at −30° C. under a nitrogen atmosphere. The solution was left tostir overnight at room temperature, then diluted with CH₂Cl₂ (20 mL) andwashed with water (3×10 mL) with back-extraction. The combined organicextracts were dried over Na₂SO₄, filtered and concentrated under reducedpressure. The crude product was purified by column chromatography(cyclohexane-diethyl ether, 50:50) to afford the title product (3.30 g,89%) as a colorless oil. ¹H NMR (400 MHz, CDCl₃) δ 7.47-7.30 (m, 5H),5.97-5.50 (m, 1H), 5.23-5.08 (m, 2H), 4.49 (br. s., 1H), 4.07-3.21 (m,10H), 1.97-1.73 (m, 4H), 1.49-1.38 (m, 9H). LC-MS (Method A): m/z=437.5[M+H]⁺, 1.18 min.

Step 2: Preparation of methyl(2S)-2-{[(benzyloxy)carbonyl]amino}-3-[(2S)-pyrrolidin-2-ylmethoxy]propanoate

A solution of tert-butyl(2S)-2-{[(2S)-2-{[(benzyloxy)carbonyl](methyl)amino}-3-methoxy-3-oxopropoxy]methyl}pyrrolidine-1-carboxylate(450 mg, 1.03 mmol) in CH₂Cl₂ (5 mL) and TFA (5 mL) was stirred at 0° C.for 3 h. The reaction mixture was concentrated under reduced pressureand the crude product was purified by column cromatography on KP-NHmodified silica (cyclohexane-EtOAc, 80:20 to 60:40 then neat MeOH) toafford the title compound (313 mg, 90%) as a colorless oil. ¹H NMR (400MHz, CDCl₃) δ 7.48-7.29 (m, 5H), 6.23 (br. s., 1H), 5.22-5.10 (m, 2H),4.50 (br. s., 1H), 3.96 (dd, J=9.9, 3.1 Hz, 1H), 3.78 (s, 3H), 3.72 (dd,J=9.8, 3.3 Hz, 1H), 3.51-3.44 (m, 1H), 3.39-3.32 (m, 1H), 3.25 (dq,J=4.5, 7.0 Hz, 1H), 3.02-2.93 (m, 1H), 2.91-2.81 (m, 1H), 1.87-1.63 (m,3H), 1.44-1.32 (m, 1H). LC-MS (Method A): m/z=337.3 [M+H]⁺, 0.49 min.

Step 3: Preparation of benzylN-[(4S,9aS)-5-oxo-octahydropyrrolo[2,1-c][1,4]oxazepin-4-yl]carbamate

Trimethylaluminum solution (2M in heptane, 0.56 mL, 1.12 mmol) was addeddropwise to a stirred solution of methyl(2S)-2-{[(benzyloxy)carbonyl]amino}-3-[(2S)-pyrrolidin-2-ylmethoxy]propanoate(313 mg, 0.93 mmol) in CH₂Cl₂ (5 mL) at −30° C. The solution was left towarm to room temperature and left to stir at room temperature for 1 h.The reaction was cooled to 0° C. and 1N HCl aqueous solution (4.63 mL,4.63 mmol) and water (5 mL) were added. The phases were separated andthe aqueous fraction was extracted twice with CH₂Cl₂, filtered through ahydrophobic frit (Phase Separator) and concentrated under reducedpressure. The crude product was purified by column chromatography(CH₂Cl₂-MeOH, 95:5) to give the title compound (217 mg, 77%) as acolorless oil. ¹H NMR (400 MHz, CDCl₃) δ 7.45-7.29 (m, 5H), 5.73 (br.s., 1H), 5.14 (br. s., 2H), 4.41 (br. s., 1H), 4.18-3.89 (m, 3H),3.82-3.58 (m, 2H), 3.54-3.19 (m, 2H), 2.18-2.04 (m, 1H), 1.97-1.83 (m,1H), 1.81-1.64 (m, 1H), 1.56-1.39 (m, 1H). LC-MS (Method A): m/z=305.3[M+H]⁺, 0.74 min.

Step 4: Preparation of(4S,9aS)-4-amino-octahydropyrrolo[2,1-c][1,4]oxazepin-5-one

Palladium on carbon (10%, 75 mg) was added to a solution of benzylN-[(4S,9aS)-5-oxo-octahydropyrrolo[2,1-c][1,4]oxazepin-4-yl]carbamate(215 mg, 0.71 mmol) in MeOH (5 mL) under a nitrogen atmosphere. Theatmosphere of nitrogen was replaced with an atmosphere of hydrogen andthe reaction was stirred for 15 h. The reaction was quenched byfiltration through a Celite plug, washing with abundant MeOH. Thefiltrate was concentrated under reduced pressure to give the titlecompound (116 mg, 96%) which was used directly in the next step. ¹H NMR(400 MHz, CDCl₃) δ 4.23-4.11 (m, 1H), 4.02 (dd, J=12.5, 1.3 Hz, 1H),3.93 (dd, J=12.8, 4.5 Hz, 1H), 3.80-3.68 (m, 2H), 3.64 (dd, J=4.4, 0.9Hz, 1H), 3.41 (ddd, J=11.9, 10.4, 6.8 Hz, 1H), 3.23 (dd, J=12.7, 9.4 Hz,1H), 2.18-2.08 (m, 1H), 2.00-1.87 (m, 1H), 1.86-1.68 (m, 1H), 1.57-1.44(m, 1H). LC-MS (Method B): m/z=171.1 [M+H]⁺, 0.35 min.

Step 5: Preparation of5-benzyl-N-((4S,9aS)-5-oxohexahydro-1H,3H-pyrrolo[2,1-c][1,4]oxazepin-4-yl)-4H-1,2,4-triazole-3-carboxamide

To a suspension of 5-benzyl-4H-1,2,4-triazole-3-carboxylic acid (50 mg,0.246 mmol) and(4S,9aS)-4-amino-octahydropyrrolo[2,1-c][1,4]oxazepin-5-one (42 mg,0.246 mmol), in CH₂Cl₂ (2 mL) was added N,N-diisopropylethylamine (0.107mL, 0.49 mmol). The reaction mixture was stirred for 10 minutes, andthen T3P solution (50 wt % in EtOAc, 0.22 mL, 0.37 mmol) was added.After 40 minutes the reaction mixture was quenched by adding water, andthe two phases were separated. The organic phase was washed with 0.5 NHCl solution, sat. NaHCO₃ solution, and brine, and concentrated underreduced pressure. The crude product was purified by columnchromatography (CH₂Cl₂-MeOH, 90:10 to 70:30) to afford the titlecompound. ¹H NMR (400 MHz, CDCl₃) δ 8.05 (d, J=6.3 Hz, 1H), 7.40-7.17(m, 5H), 4.72 (dd, J=6.9, 4.9 Hz, 1H), 4.33-4.03 (m, 5H), 3.84 (d,J=12.8 Hz, 1H), 3.75-3.62 (m, 1H), 3.43 (dt, J=6.8, 11.2 Hz, 1H), 3.31(dd, J=12.8, 9.5 Hz, 1H), 2.21-2.08 (m, 1H), 1.95-1.83 (m, 1H),1.81-1.64 (m, 1H), 1.58-1.43 (m, 1H). LC-MS (Method A): m/z=356.3[M+H]⁺, 0.67 min.

Example 28 and 29:5-benzyl-N-((3R,4S)-4-fluoro-1-methyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-3-yl)isoxazole-3-carboxamideand5-benzyl-N-((3S,4R)-4-fluoro-1-methyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-3-yl)isoxazole-3-carboxamide(28); and5-benzyl-N-((3R,4R)-4-fluoro-1-methyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-3-yl)isoxazole-3-carboxamideand5-benzyl-N-((3S,4S)-4-fluoro-1-methyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-3-yl)isoxazole-3-carboxamide(29)

Example 30:(S)-5-benzyl-N-(5,6-dihydro-4H-benzo[f]imidazo[1,2-a]azepin-4-yl)isoxazole-3-carboxamide

Step 1: Preparation of 3-amino-2,3,4,5-tetrahydro-1H-1-benzazepin-2-one

To a solution of 3-iodo-2,3,4,5-tetrahydro-1H-1-benzazepin-2-one (4.50g, 15.7 mmol) in N,N-dimethylformamide (20 mL) was added sodium azide(1.23 g, 18.8 mmol) and the reaction mixture was stirred at roomtemperature. Precipitate formed after 30 minutes. The reaction mixturewas diluted with water (300 mL). More solids precipitated and themixture was stirred for an additional 10 minutes. The solid wascollected by filtration, washed with water (20 mL), and dried in vacuo.The crude product was dissolved in tetrahydrofuran (30 mL) and water(0.5 mL). Triphenylphosphine (4.50 g, 17.2 mmol) was added and thereaction mixture was stirred at room temperature for 3 hours. Solidswere removed by filtration. The filtrate was dried over anhydrous sodiumsulfate and concentrated to afford the title compound (2.00 g, 72%) as awhite solid. LC-MS (Method E): m/z=177.0 [M+H]⁺, 0.413 min.

Step 2: Preparation of(3S)-3-amino-2,3,4,5-tetrahydro-1H-1-benzazepin-2-one

To a solution of 3-amino-2,3,4,5-tetrahydro-1H-1-benzazepin-2-one (1.85g, 11.0 mmol) in isopropanol (200 mL) at 70° C. was added L-pyroglutamicacid (1.42 g, 11.0 mmol) followed by 2-hydroxy-5-nitrobenzaldehyde (0.06g, 0.33 mmol). The reaction mixture was stirred at 70° C. for 4 days.After cooling to room temperature, the solid was collected byfiltration, rinsed with isopropanol and the filtrate was basified withammonium hydroxide (28%, 10 mL). The resulting solution was extractedwith dichloromethane (4×100 mL). The combined organic layers were washedwith brine, dried over anhydrous sodium sulfate and concentrated toafford the title compound (0.91 g, 49%) as a white solid. LC-MS (MethodE): m/z=177.0 [M+H]⁺, 0.421 min.

Step 3: Preparation of benzylN-((3S)-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepin-3-yl)carbamate

A solution of potassium carbonate (2.00 g, 15 mmol) in water (4 mL) wasadded to a solution of(3S)-3-amino-2,3,4,5-tetrahydro-1H-1-benzazepin-2-one (0.5 g, 3 mmol) indichloromethane (30 mL) and then benzyl chloroformate (0.77 g, 4.5 mmol)was added. The reaction mixture was stirred at room temperature for 16hours. The organic layer was separated, washed with brine, dried overanhydrous sodium sulfate, filtered and concentrated under vacuum toafford the title compound (0.87 g, 99%) as a white solid. LC-MS (MethodE): m/z=311.0 [M+H]⁺, 0.838 min.

Step 4: Preparation of benzylN-((3S)-2-sulfanylidene-2,3,4,5-tetrahydro-1H-1-benzazepin-3-yl)carbamate

Lawesson's reagent (1.05 g, 2.6 mmol) was added to a solution of benzylN-((3S)-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepin-3-yl)carbamate (0.80 g,2.6 mmol) in tetrahydrofuran (40 mL) and the reaction mixture wasstirred under a nitrogen atmosphere for 16 hours at room temperature.The precipitate was removed by filtration. The filtrate was concentratedunder reduced pressure. The resulting residue was diluted with water (50mL) and extracted with ethyl acetate (3×50 mL). The combined organiclayers were washed with brine, dried over sodium sulfate, filtered andconcentrated under reduced pressure to give the crude title compound(0.82 g, 98%) as a white solid. LC-MS (Method E): m/z=349.1 [M+Na]⁺,0.946 min.

Step 5: Preparation of benzylN-((3S)-2-((2,2-dimethoxyethyl)amino)-4,5-dihydro-3H-1-benzazepin-3-yl)carbamate

2,2-Dimethoxyethanamine (1.06 g, 10.1 mmol) was added to a mixture ofbenzylN-((3S)-2-sulfanylidene-2,3,4,5-tetrahydro-1H-1-benzazepin-3-yl)carbamate(0.81 g, 2.5 mmol) and mercury dichloride (0.89 g, 3.3 mmol) intetrahydrofuran (25 mL). The resulting mixture was heated for 20 minutesat 55° C. After cooling to room temperature, the solids were removed byfiltration and the filtrate was concentrated under reduced pressure. Theresulting residue was diluted with water (20 mL) and extracted withdichloromethane (3×100 mL). The combined organic layers were washed withbrine, dried over anhydrous sodium sulfate, filtered and concentratedunder reduced pressure to give the title compound (0.89 g, 90%) as alight yellow solid. LC-MS (Method C): m/z=398.2 [M+H]⁺, 1.182 min.

Step 6: Preparation of (S)-benzyl(5,6-dihydro-4H-benzo[f]imidazo[1,2-a]azepin-4-yl)carbamate

A solution of benzylN-((3S)-2-((2,2-dimethoxyethyl)amino)-4,5-dihydro-3H-1-benzazepin-3-yl)carbamate(0.85 g, 3 mmol) in formic acid (8 mL, 96%) was heated for 2 hours at100° C. The black sediment was removed by filtration and the filtratewas concentrated under reduced pressure. The resulting residue wasdiluted with water (50 mL), basified with aqueous sodium hydroxide (1 N,30 mL) and extracted with ethyl acetate (3×50 mL). The combined organiclayers were washed with brine, dried over anhydrous sodium sulfate,filtered and concentrated under reduced pressure. The residue waspurified by column chromatography (ethyl acetate/petroleum ether, 1/3)to afford the title compound (0.68 g, 95%) as a white solid. LC-MS(Method E): m/z=334.0 [M+H]⁺, 0.671 min.

Step 7. Preparation of(S)-5,6-dihydro-4H-benzo[f]imidazo[1,2-a]azepin-4-amine

A solution of (S)-benzyl(5,6-dihydro-4H-benzo[f]imidazo[1,2-a]azepin-4-yl)carbamate (0.68 g, 2mmol) in ethanol (20 mL) was aged overnight in the presence of palladiumon carbon (10%, 0.5 g) under an hydrogen atmosphere (2-3 atm). Thereaction mixture was filtered through Celite and the filtrate wasconcentrated under reduced pressure to afford the title compound (0.40g, 99%) as a yellow oil. LC-MS (Method C): m/z=200.1 [M+H]⁺, 0.915 min.

Step 8: Preparation of(S)-5-benzyl-N-(5,6-dihydro-4H-benzo[f]imidazo[1,2-a]azepin-4-yl)isoxazole-3-carboxamide

The crude product obtained using Amide Coupling Procedure C was purifiedby Prep-HPLC with the following conditions: Column, XBridge Prep C18 OBDColumn, 5 μm, 19×150 mm; mobile phase, water (0.1% formic acid) and ACN(45.0% ACN to 70.0% over 7 min); Detector, UV 254/220 nm to afford thetitle compound. ¹H NMR (300 MHz, DMSO-d₆) δ 9.00 (d, J=7.8 Hz, 1H), 7.49(d, J=1.5 Hz, 1H), 7.46-7.41 (m, 3H), 7.40-7.21 (m, 6H), 6.96 (d, J=1.5Hz, 1H), 6.53 (s, 1H), 4.80 (dd, J=10.2, 7.5 Hz, 1H), 4.18 (s, 2H), 2.72(dd, J=11.7, 6.0 Hz, 1H), 2.45-2.27 (m, 3H). LC-MS (Method O): m/z=385.0[M+H]⁺, 1.587 min.

Example 31 and 34:5-benzyl-N-((3R,4R)-4-fluoro-1-methyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-3-yl)-4H-1,2,4-triazole-3-carboxamideand5-benzyl-N-((3S,4S)-4-fluoro-1-methyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-3-yl)-4H-1,2,4-triazole-3-carboxamide(31); and5-benzyl-N-((3R,4S)-4-fluoro-1-methyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-3-yl)-4H-1,2,4-triazole-3-carboxamideand5-benzyl-N-((3S,4R)-4-fluoro-1-methyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-3-yl)-4H-1,2,4-triazole-3-carboxamide(34)

Example 32:(S)-5-benzyl-N-(9-chloro-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4H-1,2,4-triazole-3-carboxamide

Step 1: Preparation of(2S)-2-(((tert-butoxy)carbonyl)amino)-3-(2-chloro-6-nitrophenoxy)propanoicacid

Sodium hydride (60%, 0.39 g, 97.6 mmol) was added to a solution of(S)-2-(tert-butoxycarbonylamino)-3-hydroxypropanoic acid (10.0 g, 48.8mmol) in N,N-dimethylformamide (50 mL) under nitrogen atmosphere. Afterstirring for 2 hours at 0° C., 1-chloro-2-fluoro-3-nitrobenzene (8.6 g,48.8 mmol) was added. The reaction mixture was stirred overnight at roomtemperature, quenched with hydrochloric acid (0.5 M, 50 mL) andextracted with ethyl acetate (3×50 mL). The combined organic layers werewashed with brine, dried over anhydrous sodium sulfate, filtered andconcentrated under reduced pressure. The resulting residue was purifiedby reverse phase column chromatography using an RP-C18 column(acetonitrile/water, 7/3) to afford the title compound (5.5 g, 31%) as ayellow solid. LC-MS (Method G): m/z=361.0 [M+H]⁺, 0.665 min.

Step 2: Preparation of(2S)-3-(2-amino-6-chlorophenoxy)-2-(((tert-butoxy)carbonyl)amino)propanoicacid

Zinc (8.13 g, 125 mmol) and ammonium chloride (6.70 g, 125 mmol) wereadded to a stirred solution of(2S)-2-(((tert-butoxy)carbonyl)amino)-3-(2-chloro-6-nitrophenoxy)propanoicacid (4.5 g, 12.5 mmol) in methanol/tetrahydrofuran (100 mL, 1/1). Theresulting mixture was stirred for 2 hours at 25° C. Solids were removedby filtration and the filtrate was concentrated under reduced pressureto afford the title compound (4 g crude) as a white solid, which wasused directly in the next step without further purification. LC-MS(Method G): m/z=331.0 [M+H]⁺, 0.704 min.

Step 3: Preparation of tert-butylN-((3S)-9-chloro-4-oxo-2,3,4,5-tetrahydro-1,5-benzoxazepin-3-yl)carbamate

2-(7-Aza-1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluroniumhexafluorophosphate (1.1 g, 2.91 mmol) and ethyldiisopropylamine (0.94g, 7.26 mmol) were added to a stirred solution of(2S)-3-(2-amino-6-chlorophenoxy)-2-(((tert-butoxy)carbonyl)amino)propanoicacid (0.80 g, 2.42 mmol) in N,N-dimethylformamide (10 mL). Afterstirring for 2 hours at room temperature, the reaction mixture wasdiluted with water (50 mL) and extracted with ethyl acetate (3×40 mL).The combined organic layers were washed with brine, dried over anhydroussodium sulfate, filtered and concentrated under reduced pressure. Theresidue was purified by column chromatography (ethyl acetate/petroleumether, 1/6) to afford the title compound (0.18 g, 24%) as a yellowsolid. LC-MS (Method G): m/z=313.0 [M+H]⁺, 1.006 min.

Step 4: Preparation of tert-butylN-((3S)-9-chloro-5-methyl-4-oxo-2,3,4,5-tetrahydro-1,5-benzoxazepin-3-yl)carbamate

Iodomethane (82 mg, 0.58 mmol) was added dropwise to a stirred mixtureof tert-butylN-((3S)-9-chloro-4-oxo-2,3,4,5-tetrahydro-1,5-benzoxazepin-3-yl)carbamate(180 mg, 0.58 mmol) and cesium carbonate (188 mg, 0.58 mmol) inN,N-dimethylformamide (10 mL). After stirring for 2 hours at roomtemperature, the reaction mixture was quenched with water (50 mL) andextracted with ethyl acetate (3×50 mL). The combined organic layers werewashed with brine, dried over anhydrous sodium sulfate, filtered andconcentrated under reduced pressure. The residue was purified by columnchromatography (ethyl acetate/petroleum ether, 1/6) to afford the titlecompound (120 mg, 64%) as a white solid. LC-MS (Method G): m/z=327.0[M+H]⁺, 1.045 min.

Step 5: Preparation of(3S)-3-amino-9-chloro-5-methyl-2,3,4,5-tetrahydro-1,5-benzoxazepin-4-onehydrochloride

tert-butylN-((3S)-9-chloro-5-methyl-4-oxo-2,3,4,5-tetrahydro-1,5-benzoxazepin-3-yl)carbamate(120 mg, 0.37 mmol) was added to a solution of hydrogen chloride indioxane (4 M, 10 mL). The reaction mixture was stirred for 1 hour atroom temperature and concentrated under reduced pressure to afford thetitle compound (83 mg crude) as a white solid. LC-MS (Method G):m/z=227.0 [M+H]⁺, 0.772 min.

Step 6: Preparation of(S)-5-benzyl-N-(9-chloro-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4H-1,2,4-triazole-3-carboxamide

The crude product obtained using Amide Coupling Procedure C was purifiedby Prep-HPLC with the following conditions: Column, Xbridge Phenyl OBDColumn, 5 μm, 19×150 mm; mobile phase, water (10 mmol/L NH₄HCO₃) and ACN(50.0% ACN to 70.0% over 7 min); Detector, UV 254 & 220 nm to afford thetitle compound. ¹H NMR (400 MHz, CD₃OD) δ 7.44-7.20 (m, 8H), 4.98 (dd,J=15.2, 10.0 Hz, 1H), 4.68 (dd, J=13.2, 10.0 Hz, 1H), 4.46 (dd, J=15.2,13.2 Hz, 1H), 4.17 (s, 2H), 3.42 (s, 3H). LC-MS (Method Q): m/z=412.2[M+H]⁺, 1.336 min.

Example 33:(S)-1-benzyl-N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)azetidine-3-carboxamide

The crude product obtained using Amide Coupling Procedure C was purifiedby Prep-HPLC with the following conditions: Column, Xbridge Prep C18 OBDColumn, 5 μm, 19×150 mm; mobile phase, water (10 mmol/L NH₄HCO₃) and ACN(30.0% ACN to 60.0% over 7 min); Detector, UV 254 & 220 nm to afford thetitle compound. ¹H NMR (300 MHz, CDCl₃) δ 7.29 (s, 4H), 7.19 (m, 4H),7.06 (d, J=6.9 Hz, 1H), 4.95-4.80 (m, 1H), 4.67 (dd, J=9.6, 7.5 Hz, 1H),4.14 (dd, J=11.1, 9.6 Hz, 1H), 3.65 (s, 2H), 3.57 (s, 2H), 3.51 (s, 3H),3.34 (m, 2H), 3.22-3.02 (m, 1H). LC-MS (Method O): m/z=365.9 [M+H]⁺,1.215 min.

Example 35:(S)—N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-5-(1-phenylcyclopropyl)-4H-1,2,4-triazole-3-carboxamide

Step 1: Preparation of 1-phenylcyclopropane-1-carbohydrazide

A solution of hydrazine in tetrahydrofuran (1 M, 30 mL) was added to asolution of 1-phenylcyclopropane-1-carboxylic acid (0.48 g, 3.00 mmol),2-(7-aza-1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluroniumhexafluorophosphate (1.37 g, 3.60 mmol) and ethyldiisopropylamine (1.16g, 8.98 mmol) in N,N-dimethylformamide (10 mL). After stirring for 1hour at room temperature, the reaction mixture was diluted with water(20 mL), and extracted with ethyl acetate (3×20 mL). The combinedorganic layers were washed with brine, dried over anhydrous sodiumsulfate, filtered and concentrated under reduced pressure. The residuewas purified by column chromatography (ethyl acetate/petroleum ether,1/2) to afford the title compound (0.53 g, 98%) as a yellow oil. LC-MS(Method R: m/z=177.2 [M+H]⁺, 0.670 min.

Step 2: Preparation of ethyl2-amino-2-(((1-phenylcyclopropyl)formamido)imino)acetate

Ethyl 2-ethoxy-2-iminoacetate (452 mg, 3.11 mmol) was added to a stirredsolution of 1-phenylcyclopropane-1-carbohydrazide (528 mg, 3.00 mmol) inethanol/ether (12 mL, 1/3). The reaction mixture was stirred for 2 hoursat room temperature. The yellow solid was collected by filtration toafford the title compound (300 mg, 36%). LC-MS (Method S: m/z=276.2[M+H]⁺, 0.663 min.

Step 3: Preparation of ethyl5-(1-phenylcyclopropyl)-4H-1,2,4-triazole-3-carboxylate

A solution of ethyl2-amino-2-(((1-phenylcyclopropyl)formamido)imino)acetate (275 mg, 1.00mmol) in xylene (10 mL) was irradiated with microwave radiation for 10hours at 170° C. The reaction mixture was concentrated under reducedpressure. The residue was purified by column chromatography (ethylacetate/petroleum ether, 1/4) to afford the title compound (100 mg, 39%)as a yellow solid. LC-MS (Method C): m/z=258.1 [M+H]⁺, 1.641 min.

Step 4: Preparation of5-(1-phenylcyclopropyl)-4H-1,2,4-triazole-3-carboxylic acid

A solution of lithium hydroxide (28 mg, 1.17 mmol) in water (1 mL) wasadded into a solution of ethyl5-(1-phenylcyclopropyl)-4H-1,2,4-triazole-3-carboxylate (100 mg, 0.39mmol) in tetrahydrofuran (3 mL) and the resulting mixture was stirredovernight at room temperature. After adjusting the pH to 6-7 withaqueous hydrochloride acid (1 N, 20 mL), the reaction mixture wasextracted with ethyl acetate (3×10 mL). The combined organic layers werewashed with brine, dried over anhydrous sodium sulfate, filtered andconcentrated under reduced pressure to afford the title compound (90 mgcrude) as a yellow solid, which was used directly in the next stepwithout further purification. LC-MS (Method R): m/z=230.2 [M+H]⁺, 0.530min.

Step 5: Preparation of(S)—N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-5-(1-phenylcyclopropyl)-4H-1,2,4-triazole-3-carboxamide

The crude product obtained using Amide Coupling Procedure C was purifiedby Prep-HPLC with the following conditions: Column, Xbridge Phenyl OBDColumn, 5 μm, 19×150 mm; mobile phase, water (10 mmol/L NH₄HCO₃) and ACN(50.0% ACN to 70.0% over 7 min); Detector, UV 254 & 220 nm to afford thetitle compound. ¹H NMR (400 MHz, CD₃OD) δ 7.44-7.20 (m, 9H), 4.99 (dd,J=11.6, 7.6 Hz, 1H), 4.58 (dd, J=9.6, 7.6 Hz, 1H), 4.39 (dd, J=11.6,10.0 Hz, 1H), 3.57 (s, 3H), 1.67-1.56 (m, 2H), 1.46-1.29 (m, 2H). LC-MS(Method D): m/z=404.1 [M+H]⁺, 1.966 min.

Example 36:5-benzyl-N-(1-methyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo[4,5]imidazo[1,2-a][1,3]diazepin-3-yl)isoxazole-3-carboxamide

Example 37:(R)-5-benzyl-N-(4,4-difluoro-1-methyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-3-yl)-4H-1,2,4-triazole-3-carboxamide

Example 38A and 38B:(S)-5-benzyl-N-(2,4-dimethyl-5-oxo-5,6,7,8-tetrahydro-4H-thiazolo[4,5-b]azepin-6-yl)-4H-1,2,4-triazole-3-carboxamideand(R)-5-benzyl-N-(2,4-dimethyl-5-oxo-5,6,7,8-tetrahydro-4H-thiazolo[4,5-b]azepin-6-yl)-4H-1,2,4-triazole-3-carboxamide

Step 1: Preparation of azepane-2,7-dione

A stirring solution of azepan-2-one (11.3 g, 100 mmol),2-hydroxyisoindoline-1,3-dione (1.63 g, 10 mmol), and cobalt acetate(88.5 mg, 0.5 mmol) in acetonitrile (100 mL) was flushed with oxygen(balloon). The reaction mixture was heated overnight at 85° C. under anoxygen atmosphere. The solids were removed by filtration and thefiltrate was concentrated under vacuum. The residue was purified bycolumn chromatography (ethyl acetate/petroleum ether, 1/3) to afford thetitle compound (3.70 g, 29.1%) as a white solid. LC-MS (Method C):m/z=128.2 [M+H]⁺, 0.683 min.

Step 2: Preparation of 1-methylazepane-2,7-dione

Iodomethane (1.68 g, 11.8 mmol) was added dropwise to a stirring mixtureof azepane-2,7-dione (1.50 g, 11.8 mmol) and cesium carbonate (3.85 g,5.0 mmol) in N,N-dimethylformamide (25 mL) at 0° C. The reaction mixturewas stirred overnight at room temperature, quenched by the addition ofwater (50 mL) and extracted with ethyl acetate (3×50 mL). The combinedorganic layers were washed with brine, dried over anhydrous sodiumsulfate, filtered and concentrated under vacuum. The residue waspurified by column chromatography (ethyl acetate/petroleum ether, 1/4)to afford the title compound (1.1 g, 66.1%) as a yellow oil. LC-MS(Method C): m/z=142.1 [M+H]⁺, 0.863 min.

Step 3: Preparation of 3-bromo-1-methylazepane-2,7-dione

Bromine (632 mg, 4.00 mmol) was added to a stirring solution of1-methylazepane-2,7-dione (564 mg, 4.0 mmol) in chloroform (10 mL). Thereaction mixture was stirred at 110° C. for 1.5 hours in a sealed tube.The reaction mixture was concentrated under high vacuum to afford thetitle compound (600 mg crude) as a brown oil. LC-MS (Method C):m/z=220.1 [M+H]⁺, 0.940 min.

Step 4: Preparation of2,4-dimethyl-7,8-dihydro-4H-thiazolo[4,5-b]azepin-5(6H)-one

Ethanethioamide (300 mg, 4.0 mmol) was added to a solution of3-bromo-1-methylazepane-2,7-dione (600 mg, 4.0 mmol) in pyridine (10mL). The reaction mixture was stirred at 50° C. for 16 hours, quenchedby the addition of water (20 mL) and extracted with ethyl acetate (3×50mL). The combined organic layers were washed with brine, dried overanhydrous sodium sulfate, filtered and concentrated under vacuum. Theresidue was purified by column chromatography (ethyl acetate/petroleumether, 1/4) to afford the title compound (70 mg, 9%) as a yellow solid.LC-MS (Method C): m/z=197.1 [M+H]⁺, 0.981 min.

Step 5: Preparation of6-iodo-2,4-dimethyl-7,8-dihydro-4H-thiazolo[4,5-b]azepin-5(6H)-one

N¹,N¹,N²,N²-tetramethylethane-1,2-diamine (124 mg, 1.07 mmol) was addedto a stirring solution of2,4-dimethyl-7,8-dihydro-4H-thiazolo[4,5-b]azepin-5(6H)-one (70 mg, 0.36mmol) in dichloromethane (5 mL) at 0° C. followed by the addition ofiodotrimethylsilane (214 mg, 1.07 mmol). The reaction mixture wasstirred for 1 hour at 0° C. After adding iodine (137.2 mg, 0.54 mmol),the reaction mixture was stirred for another 2 hours at 0° C. andquenched with aqueous sodium thiosulfate (5%, 15 mL). The resultingsolution was stirred for an additional 15 minutes and extracted withethyl acetate (3×20 mL). The combined organic layers were washed withbrine, dried over anhydrous sodium sulfate, filtered and concentratedunder vacuum to afford the title compound (61 mg crude) as a yellowsolid, which was used directly in the next step without furtherpurification. LC-MS (Method R): m/z=323.2[M+H]⁺, 0.820 min.

Step 6: Preparation of6-amino-2,4-dimethyl-7,8-dihydro-4H-thiazolo[4,5-b]azepin-5(6H)-one

To a solution of6-iodo-2,4-dimethyl-7,8-dihydro-4H-thiazolo[4,5-b]azepin-5(6H)-one (61mg, 0.19 mmol) in N,N-dimethylformamide (2 mL) was added sodium azide(37.1 mg, 0.57 mmol). The reaction mixture was stirred for 1 hour atroom temperature and concentrated under reduced pressure. The residuewas dissolved in tetrahydrofuran (3 mL) and water (1 mL) andtriphenylphosphine (149.3 mg, 0.57 mmol) was added in one portion. Thereaction mixture was stirred at 50° C. overnight, diluted with water (10mL) and extracted with ethyl acetate (3×20 mL). The combined organiclayers were washed with brine, dried over anhydrous sodium sulfate,filtered and concentrated under vacuum. The residue was purified bycolumn chromatography (methanol/dichloromethane, 1/10) to afford thetitle compound (33 mg, 83%) as a yellow solid. LC-MS (Method C):m/z=212.1 [M+H]⁺, 0.735 min.

Step 7. Preparation of5-benzyl-N-(2,4-dimethyl-5-oxo-5,6,7,8-tetrahydro-4H-thiazolo[4,5-b]azepin-6-yl)-4H-1,2,4-triazole-3-carboxamide

The crude product obtained using Amide Coupling Procedure C was purifiedby Prep-HPLC with the following conditions: column: X bridge Prep C18,19×150 mm, 5 μm; Mobile phase: Phase A: water (10 mmol/L NH₄HCO₃); PhaseB: ACN (20% to 80% over 12 min); Detector, UV 220 & 254 nm to afford thetitle compound. LC-MS (Method R): m/z=397.1 [M+H]⁺, 1.095 min.

Step 8: Preparation of(R)-5-benzyl-N-(2,4-dimethyl-5-oxo-5,6,7,8-tetrahydro-4H-thiazolo[4,5-b]azepin-6-yl)-4H-1,2,4-triazole-3-carboxamide(First Eluting Isomer) and(S)-5-benzyl-N-(2,4-dimethyl-5-oxo-5,6,7,8-tetrahydro-4H-thiazolo[4,5-b]azepin-6-yl)-4H-1,2,4-triazole-3-carboxamide(Second Eluting Isomer)

The enantiomers of5-benzyl-N-(2,4-dimethyl-5-oxo-5,6,7,8-tetrahydro-4H-thiazolo[4,5-b]azepin-6-yl)-4H-1,2,4-triazole-3-carboxamide(24 mg, 0.06 mmol) were separated by Prep-Chiral-HPLC with the followingconditions: Column: Chiralpak IA, 2×25 cm, 5 μm; Mobile Phase A:hexanes, Mobile Phase B: EtOH; Flow rate: 15 mL/min; Gradient: 50% B to50% B over 17.5 min; UV 220 & 254 nm; RT 1:10.18 min; RT 2: 15.13 min toafford the title compounds:

Example 38B (first eluting isomer): ¹H NMR (400 MHz, Methanol-d₄) δ7.36-7.25 (m, 5H), 4.73-4.69 (m, 1H), 4.18 (s, 2H), 3.39 (s, 3H),3.05-2.88 (m, 2H), 2.73-2.64 (m, 4H), 2.36-2.27 (m, 1H). LC-MS (MethodD): m/z=397.1 [M+H]⁺, 1.623 min.

Example 38A (second eluting isomer): ¹H NMR (400 MHz, Methanol-d₄) δ7.36-7.24 (m, 5H), 4.73-4.68 (m, 1H), 4.18 (s, 2H), 3.39 (s, 3H),3.06-2.87 (m, 2H), 2.73-2.63 (m, 4H), 2.36-2.27 (m, 1H). LC-MS (MethodD): m/z=397.1 [M+H]⁺, 1.623 min.

Example 39:(S)-5-benzyl-N-(1-methyl-2-oxo-8-(trifluoromethyl)-2,3,4,5-tetrahydro-1H-pyrrolo[1,2-a][1,3]diazepin-3-yl)-4H-1,2,4-triazole-3-carboxamide

Example 40:(S)-5-benzyl-N-(5-methyl-4-oxo-6-(trifluoromethyl)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4H-1,2,4-triazole-3-carboxamide

Example 41:(S)-5-benzyl-N-(1-methyl-2-oxo-1,2,3,4-tetrahydropyrido[3,4-b][1,4]oxazepin-3-yl)-4H-1,2,4-triazole-3-carboxamide

Step 1: Preparation of(2S)-2-(((tert-butoxy)carbonyl)amino)-3-((4-nitropyridin-3-yl)oxy)propanoicacid

Sodium hydride (60%, 1.92 g, 80.1 mmol) was added to a stirred solutionof (2S)-2-(tert-butoxycarbonylamino)-3-hydroxypropanoic acid (8.21 g,40.0 mmol) in dimethyl formamide (30 mL) under nitrogen atmosphere at 0°C. After stirring for 2 hours at 0° C., a solution of3-fluoro-4-nitropyridine (5.52 g, 40.0 mmol) in dimethyl formamide (10mL) was added dropwise. The reaction mixture was stirred overnight atroom temperature, quenched by the addition of water (10 mL), andextracted with ethyl acetate (3×20 mL). The combined organic layers werewashed with brine, dried over anhydrous sodium sulfate, filtered andconcentrated under reduced pressure. The residue was purified by reversephase CombiFlash using a RP-C18 column (acetonitrile/water, 1/4) toafford the title compound (2.41 g, 18%) as a yellow solid. LC-MS (MethodS): m/z=328.1 [M+H]⁺, 0.829 min.

Step 2: Preparation of(2S)-3-((4-aminopyridin-3-yl)oxy)-2-(((tert-butoxy)carbonyl)amino)propanoicacid

(2S)-2-(((tert-butoxy)carbonyl)amino)-3-((4-nitropyridin-3-yl)oxy)propanoicacid (2.41 g, 7.34 mmol) in methanol (20 mL) was aged overnight at roomtemperature in the presence of palladium on carbon (10%, 345 mg) under ahydrogen atmosphere (2-3 atm). The reaction mixture was filtered throughCelite and the filtrate was concentrated under reduced pressure toafford the title compound (1.8 g, 83%) as a yellow solid, which was useddirectly in the next step without further purification. LC-MS (MethodS): m/z=298.1 [M+H]⁺, 0.601 min.

Step 3: Preparation of tert-butylN-((3S)-2-oxo-1H,2H,3H,4H-pyrido[3,4-b][1,4]oxazepin-3-yl)carbamate

2-(7-Aza-1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluroniumhexafluorophosphate (1.5 g, 4.04 mmol) and ethyldiisopropylamine (1.30g, 10.1 mmol) were added to a stirred solution of(2S)-3-((4-aminopyridin-3-yl)oxy)-2-(((tert-butoxy)carbonyl)amino)propanoicacid (1.01 g, 3.37 mmol) in N,N-dimethylformamide (13 mL). Afterstirring for 3 hours at room temperature, the reaction mixture wasdiluted with water (15 mL), and extracted with ethyl acetate (3×15 mL).The combined organic layers were washed with brine, dried over anhydroussodium sulfate, filtered and concentrated under reduced pressure. Theresulting residue was purified by column chromatography(methanol/dichloromethane, 1/10) to afford the title compound (0.4 g,83%) as a yellow solid. LC-MS (Method S): m/z=280.1 [M+H]⁺, 0.604 min.

Step 4: Preparation of tert-butylN-((3S)-1-methyl-2-oxo-1H,2H,3H,4H-pyrido[3,4-b][1,4]oxazepin-3-yl)carbamate

Iodomethane (203 mg, 1.43 mmol) was added dropwise to a mixture oftert-butylN-((3S)-2-oxo-1H,2H,3H,4H-pyrido[3,4-b][1,4]oxazepin-3-yl)carbamate (400mg, 1.43 mmol) and cesium carbonate (467 mg, 1.43 mmol) inN,N-dimethylformamide (7 mL). After stirring for 10 minutes at 0° C.,the reaction mixture was diluted with water (15 mL), and extracted withethyl acetate (3×15 mL). The combined organic layers were washed withbrine, dried over anhydrous sodium sulfate, filtered and concentratedunder reduced pressure. The residue was purified by columnchromatography (ethyl acetate/petroleum ether, 1/3) to afford the titlecompound (300 mg, 72%) as a yellow solid. LC-MS (Method S): m/z=294.1[M+H]⁺, 0.650 min.

Step 5: Preparation of(3S)-3-amino-1-methyl-H,2H,3H,4H-pyrido[3,4-b][1,4]oxazepin-2-onehydrochloride

A solution of hydrogen chloride in 1,4-dioxane (4 M, 5 mL, 20 mmol) wasadded to a solution of tert-butylN-((3S)-1-methyl-2-oxo-1H,2H,3H,4H-pyrido[3,4-b][1,4]oxazepin-3-yl)carbamate(300 mg, 1.02 mmol) in 1,4-dioxane (7 mL). The reaction mixture wasstirred for 1 hour at room temperature and concentrated to afford thetitle compound (215 mg, 92%) as a white solid. LC-MS (Method S):m/z=194.1 [M+H]⁺, 0.184 min.

Step 6: Preparation of(S)-5-benzyl-N-(1-methyl-2-oxo-1,2,3,4-tetrahydropyrido[3,4-b][1,4]oxazepin-3-yl)-4H-1,2,4-triazole-3-carboxamide

A solution of(3S)-3-amino-1-methyl-1H,2H,3H,4H-pyrido[3,4-b][1,4]oxazepin-2-onehydrochloride (115 mg, 0.50 mmol) in N,N-dimethylformamide (1 mL) wasadded to a stirring solution of 5-benzyl-2H-1,2,4-triazole-3-carboxylicacid (102 mg, 0.50 mmol), ethyldiisopropylamine (129 mg, 1.00 mmol),N¹-((ethylimino)methylene)-N³,N³-dimethylpropane-1,3-diaminehydrochloride (115 mg, 0.60 mmol) and 1-hydroxybenzotriazole (92 mg,0.60 mmol) in N,N-dimethylformamide (5 mL). The reaction mixture wasstirred overnight at room temperature and concentrated under reducedpressure. The residue was purified by Prep-HPLC with the followingconditions: Column: XBridge Prep C18 OBD Column 19×150 mm 5 μm; MobilePhase A: water (10 mmol/L NH₄HCO₃), Mobile Phase B: ACN; Flow rate: 30mL/min; Gradient: 15% B to 45% B over 10 min; 254 nm. The collectedfractions were combined and concentrated under reduced pressure toafford the title compound. ¹H NMR (400 MHz, CDCl₃) δ 12.34 (s, 1H),8.54-8.46 (m, 2H), 8.06 (d, J=7.3 Hz, 1H), 7.36-7.29 (m, 5H), 7.16 (d,J=5.2 Hz, 1H), 5.09 (m, 1H), 4.77 (dd, J=10.0, 3.2 Hz, 1H), 4.41 (dd,J=11.6, 10.0 Hz, 1H), 4.20 (s, 2H), 3.46 (s, 3H). LC-MS (Method T):m/z=379.2 [M+H]⁺, 0.888 min.

Example 42:(S)-5-benzyl-N-(5-methyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepin-3-yl)-4H-1,2,4-triazole-3-carboxamide

Step 1: Preparation of(2S)-2-(((tert-butoxy)carbonyl)amino)-3-((2-nitropyridin-3-yl)oxy)propanoicacid

Sodium hydride (60%, 2 g, 50 mmol) was added into a stirring solution of(2S)-2-(tert-butoxycarbonylamino)-3-hydroxypropanoic acid (5 g, 25.0mmol) in N,N-dimethylformamide (100 mL). The resulting mixture wasstirred at 0° C. for 2 hours. 3-Fluoro-2-nitropyridine (3.6 g, 25.3mmol) was added and the reaction mixture was stirred at room temperaturefor an additional 8 hours before quenching with hydrochloric acid (3 N,5 mL). After adjusting the pH to 3-4 with hydrochloric acid (3 N, 20mL), the resulting mixture was extracted with ethyl acetate (3×100 mL).The combined organic layers were washed with brine, dried over anhydroussodium sulfate and concentrated under reduced pressure. The residue waspurified by reversed phase chromatography with a RP-C18 column(acetonitrile/water, 1/2) to afford the title compound (3.2 g, 39%) as alight yellow oil. LC-MS (Method C): m/z=272.1 [M+H-(t-BuO)]⁺, 1.269 min.

Step 2: Preparation of(2S)-3-((2-aminopyridin-3-yl)oxy)-2-(((tert-butoxy)carbonyl)amino)propanoicacid

(2S)-2-(((tert-butoxy)carbonyl)amino)-3-((2-nitropyridin-3-yl)oxy)propanoicacid (0.45 g, 1.4 mmol) in methanol (20 mL) was aged overnight at roomtemperature in the presence of palladium on carbon (10%, 0.5 g) underhydrogen atmosphere (2-3 atm). The reaction mixture was filtered throughCelite and the filtrate was concentrated under reduced pressure toafford the title compound (0.32 g, 78%) as a yellow oil. LC-MS (MethodC): m/z=298.1 [M+H]⁺, 0.982 min.

Step 3: Preparation of tert-butylN-((3S)-4-oxo-2H,3H,4H,5H-pyrido[3,2-b][1,4]oxazepin-3-yl)carbamate

N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uroniumhexafluorophospate (0.73 g, 1.92 mmol) and N,N-diisopropylethylamine(0.25 g, 1.93 mmol) were added to a stirring solution of(2S)-3-((2-aminopyridin-3-yl)oxy)-2-(((tert-butoxy)carbonyl)amino)propanoicacid (0.45 g, 1.51 mmol) in N,N-dimethylformamide (5 mL). After stirringfor 6 hours at room temperature, the reaction mixture was quenched bythe addition of water (20 mL), and extracted with ethyl acetate (3×100mL). The combined organic layers were washed with brine, dried overanhydrous sodium sulfate and concentrated under reduced pressure. Theresulting residue was purified by column chromatography(methanol/dichloromethane, 1/10) to afford the title compound (0.11 g,26%) as a white solid. LC-MS (Method C): m/z=280.1 [M+H]⁺, 1.248 min.

Step 4: Preparation of tert-butylN-((3S)-5-methyl-4-oxo-2H,3H,4H,5H-pyrido[3,2-b][1,4]oxazepin-3-yl)carbamate

Iodomethane (50 mg, 0.35 mmol) was added dropwise to a stirring solutionof tert-butylN-((3S)-4-oxo-2H,3H,4H,5H-pyrido[3,2-b][1,4]oxazepin-3-yl)carbamate (100mg, 0.36 mmol) and cesium carbonate (120 mg, 0.36 mmol) inN,N-dimethylformamide (5 mL). After stirring for 3 hours at roomtemperature, the reaction mixture was diluted with water (20 mL), andextracted with ethyl acetate (3×100 mL). The combined organic layerswere washed with brine, dried over anhydrous sodium sulfate, filteredand concentrated under reduced pressure. The residue was purified bycolumn chromatography (methanol/dichloromethane, 1/10) to afford thetitle compound (90 mg, 86%) as a white solid. LC-MS (Method C):m/z=294.1 [M+H]⁺, 1.333 min.

Step 5: Preparation of(3S)-3-amino-5-methyl-2H,3H,4H,5H-pyrido-[3,2-b][1,4]oxazepin-4-onehydrochloride

tert-butylN-((3S)-5-methyl-4-oxo-2H,3H,4H,5H-pyrido[3,2-b][1,4]oxazepin-3-yl)carbamate(90 mg, 0.31 mmol) was added to a solution of hydrogen chloride indioxane (4 M, 10 mL). The reaction mixture was stirred for 3 hours atroom temperature and concentrated under reduced pressure to afford thetitle compound (65 mg, 93%) as a white solid, which was used directly inthe next step without further purification. LC-MS (Method C): m/z=194.1[M+H]⁺, 0.847 min.

Step 6: Preparation of(S)-5-benzyl-N-(5-methyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepin-3-yl)-4H-1,2,4-triazole-3-carboxamide

A solution of(3S)-3-amino-5-methyl-2H,3H,4H,5H-pyrido-[3,2-b][1,4]oxazepin-4-onehydrochloride (55 mg, 0.24 mmol) in N,N-dimethylformamide (1 mL) wasadded to a stirring solution of 5-benzyl-2H-1,2,4-triazole-3-carboxylicacid (80 mg, 0.40 mmol), 1-hydroxy-benzotrizole (70 mg, 0.53 mmol),N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (100 mg,0.52 mmol) and N,N-diisopropylethylamine (160 mg, 1.21 mmol) inN,N-dimethylformamide (2 mL). After stirring for 8 hours at roomtemperature, the reaction mixture was quenched by the addition of water(20 mL), and extracted with ethyl acetate (3×50 mL). The combinedorganic layers were washed with brine, dried over anhydrous sodiumsulfate, filtered and concentrated under reduced pressure. The resultingresidue was purified by Prep-HPLC with the following conditions: Column,XBridge Shield RP18 OBD Column, 5 μm, 19×150 mm; mobile phase, water(0.1% formic acid) and ACN (30.0% ACN to 60.0% over 7 min); Detector, UV254 & 220 nm to afford the title compound. ¹H NMR (300 MHz, DMSO-d₆) δ14.45 (s, 1H), 8.67 (d, J=7.2 Hz, 1H), 8.37 (dd, J=4.8, 1.8 Hz, 1H),7.71 (dd, J=7.8, 1.5 Hz, 1H), 7.37-7.21 (m, 6H), 4.92-4.82 (m, 1H), 4.73(dd, J=11.4, 9.6 Hz, 1H), 4.53 (dd, J=9.6, 7.5 Hz, 1H), 4.14 (s, 2H),3.37 (s, 3H). LC-MS (Method D): m/z=379.1 [M+H]⁺, 1.611 min.

Example 43:3-benzyl-N—((S)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)cyclobutane-1-carboxamide

Step 1: Preparation of ethyl3-(phenylmethylidene)cyclobutane-1-carboxylate

A solution of n-butyllithium in hexane (2.5 M, 3.4 mL, 8.5 mmol) wasadded dropwise to a suspension of benzyltriphenylphosphonium chloride(3.3 g, 8.5 mmol) in anhydrous tetrahydrofuran (50 mL) at −60° C. Theresulting mixture was stirred at −60° C. for 0.5 hour and then allowedto warm to room temperature. Ethyl 3-oxocyclobutanecarboxylate (1.2 g,8.5 mmol) was added and the reaction mixture was heated at reflux andstirred overnight. After cooling to room temperature, the reactionmixture was quenched with water (50 mL), and extracted with ethylacetate (3×50 mL). The combined organic layers were washed with brine,dried over anhydrous sodium sulfate, filtered and concentrated underreduced pressure. The resulting residue was purified by columnchromatography (ethyl acetate/petroleum ether, 1/20) to afford the titlecompound (0.14 g, 8%) as a light yellow oil. LC-MS (Method S): m/z=217.2[M+H]⁺, 1.144 min.

Step 2: Preparation of ethyl 3-benzylcyclobutane-1-carboxylate

Ethyl 3-(phenylmethylidene)cyclobutane-1-carboxylate (130 mg, 0.6 mmol)in ethanol (5 mL) was hydrogenated in the presence of palladium oncarbon (10%, 15 mg) under a hydrogen atmosphere. After stirring for 2hours at room temperature, the reaction mixture was filtered throughCelite and the filtrate was concentrated under reduced pressure toafford the title compound (100 mg crude) as a yellow oil, which was useddirectly in the next step without further purification. LC-MS (MethodS): m/z=219.3 [M+H]⁺, 1.160 min.

Step 3: Preparation of 3-benzylcyclobutane-1-carboxylic acid

A solution of sodium hydroxide (60 mg, 1.5 mmol) in water (1 mL) wasadded into a solution of ethyl 3-benzylcyclobutane-1-carboxylate (100mg, 0.5 mmol) in tetrahydrofuran (3 mL). After stirring for 2 hours atroom temperature, the reaction mixture was diluted with water (10 mL),adjusted to pH=3 with aqueous hydrochloric acid (3 N, 10 mL) andextracted with ethyl acetate (3×10 mL). The combined organic layers werewashed with brine, dried over anhydrous sodium sulfate and concentratedunder reduced pressure to afford the crude title compound (85 mg, 97%)as a yellow oil. LC-MS (Method I): m/z=190.9 [M+H]⁺, 0.954 min.

Step 4: Preparation of3-benzyl-N—((S)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)cyclobutane-1-carboxamide

The crude product obtained using Amide Coupling Procedure C was purifiedby Prep-HPLC with the following conditions: Column, Xbridge Prep C18 OBDColumn, 5 μm, 19×150 mm; mobile phase, water (0.05% NH₃H₂O), ACN (25%ACN to 55% B over 7 min); detector, UV 254 & 220 nm to afford the titlecompound. ¹H NMR (400 MHz, CDCl₃) δ 7.29-7.13 (m, 9H), 6.41 (d, J=6.0Hz, 1H), 4.93-4.86 (m, 1H), 4.69 (t, J=7.6 Hz, 1H), 4.12 (t, J=10.0 Hz,1H), 3.44 (s, 3H), 2.88-2.69 (m, 3H), 2.48 (q, J=7.6 Hz, 1H), 2.35-2.24(m, 2H), 2.09-1.91 (m, 2H). LC-MS (Method O): m/z=365.0 [M+H]⁺, 1.585min.

Example 44:(S)-5-benzyl-N-(1-methyl-2-oxo-1,2,3,4-tetrahydrospiro[benzo[b]azepine-5,1′-cyclopropan]-3-yl)-4H-1,2,4-triazole-3-carboxamide

Step 1: Preparation of tert-butyl1-methyl-5-methylene-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-3-ylcarbamate

To a mixture of methyltriphenylphosphonium bromide (4.4 g, 12.3 mmol) intetrahydrofuran (10 mL) was added sodium hydride (60%, 0.30 g, 12.3mmol). The resulting mixture was stirred for 1 hour at 50° C. under anitrogen atmosphere. To this mixture a solution of tert-butyl1-methyl-2,5-dioxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-3-ylcarbamate(1.50 g, 4.93 mmol) in tetrahydrofuran (20 mL) was added dropwise at 50°C. After stirring overnight at 50° C., the reaction mixture was quenchedwith saturated aqueous ammonium chloride (30 mL), and extracted withethyl acetate (3×40 mL). The combined organic layers were washed withbrine, dried over anhydrous sodium sulfate, filtered and concentratedunder vacuum. The residue was purified by column chromatography (ethylacetate/petroleum ether, 1/10) to afford the title compound (600 mg,40%) as a yellow solid. LC-MS (Method C): m/z=303.2 [M+H]⁺, 1.531 min.

Step 2: Preparation of tert-butylN-[7-methyl-6-oxo-7-azatricyclo[6.4.0.0-[2,4]]dodeca-1(8),9,11-trien-5-yl]carbamate

To a solution of potassium hydroxide (2.23 g, 39.7 mmol) in water (3.3mL) was added a solution of 1-methyl-1-nitrosourea (2.05 g, 19.7 mmol)in ether (100 mL) dropwise at 0° C. The resulting mixture was stirredfor 1 hour at 0° C. and then the organic phase was separated to get thesolution of diazomethane (100 mL). To a solution of tert-butyl1-methyl-5-methylene-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-3-ylcarbamate(0.6 g, 1.99 mmol) in tetrahydrofuran (5 mL) was added the solution ofdiazomethane (100 mL) dropwise, followed by adding a mixture ofpalladium diacetate (45 mg, 0.20 mmol) in tetrahydrofuran (1 mL)dropwise at 0° C. The reaction mixture was stirred overnight at roomtemperature. The solids were removed by filtration and the filtrate wasconcentrated under vacuum. The residue was purified by columnchromatography (ethyl acetate/petroleum ether, 1/10) to afford the titlecompound (0.15 g, 24%) as a yellow solid. LC-MS (Method C): m/z=317.2[M+H]⁺, 1.531 min.

Step 3: Preparation of3-amino-1-methyl-1,2,3,4-tetrahydrospiro[1-benzazepine-5,1-cyclopropane]-2-onehydrochloride

A solution of hydrogen chloride in 1,4-dioxane (4 N, 10 mL) was added toa solution of tert-butylN-[7-methyl-6-oxo-7-azatricyclo[6.4.0.0-[2,4]]dodeca-1(8),9,11-trien-5-yl]carbamate(150 mg, 0.60 mmol) in 1,4-dioxane (2 mL). The reaction mixture wasstirred at room temperature for 2 hours and concentrated under vacuum toafford the title compound (95 mg crude) as a yellow solid. LC-MS (MethodK): m/z=217.2 [M+H]⁺, 0.635 min.

Step 4: Preparation of(3S)-3-amino-1-methyl-1,2,3,4-tetrahydrospiro[1-benzazepine-5,1-cyclopropane]-2-one(First Eluting Isomer) and(3R)-3-amino-1-methyl-1,2,3,4-tetrahydrospiro[1-benzazepine-5,1-cyclopropane]-2-one(Second Eluting Isomer)

3-Amino-1-methyl-1,2,3,4-tetrahydrospiro[1-benzazepine-5,1-cyclopropane]-2-onehydrochloride (90 mg crude) was separated by Prep-Chiral-HPLC with thefollowing conditions: Column: Phenomenex Lux Cellulose-4, AXIA Packed,2.12×25 cm, 5 μm; Mobile Phase A: hexanes (0.1% DEA), Mobile Phase B:EtOH; Flow rate: 20 mL/min; Gradient: 35% B to 35% B over 17.5 min;220/254 nm; RT1: 11.24 min; RT2: 13.82 min to afford the titlecompounds.

First eluting isomer: (36 mg, 38%) as a white solid. LC-MS (Method D):m/z=217.2 [M+H]⁺, 1.096 min.

Second eluting isomer: (46 mg, 48%) as a white solid. LC-MS (Method D):m/z=217.2 [M+H]⁺, 1.089 min.

Step 5: Preparation of(S)-5-benzyl-N-(1-methyl-2-oxo-1,2,3,4-tetrahydrospiro[benzo[b]azepine-5,1′-cyclopropan]-3-yl)-4H-1,2,4-triazole-3-carboxamide

The crude product obtained using Amide Coupling Procedure C was purifiedby Prep-HPLC with the following conditions: Column, Xbridge Phenyl OBDColumn, 5 μm, 19×150 mm; mobile phase, water (10 mmol/L NH₄HCO₃) and ACN(50.0% ACN to 70.0% in 7 min); Detector, UV 254 & 220 nm to afford thetitle compound. ¹H NMR (300 MHz, DMSO-d₆) δ 8.20 (d, J=7.5 Hz, 1H),7.45-7.32 (m, 2H), 7.35-7.20 (m, 7H), 4.46-4.36 (m, 1H), 4.07 (s, 2H),3.30 (s, 3H), 2.71-2.65 (m, 1H), 1.57 (t, J=12.6 Hz, 1H), 1.10-1.07 (m,1H), 0.75-0.63 (m, 2H), 0.42-0.37 (m, 1H). LC-MS (Method D): m/z=402.2[M+H]⁺, 1.871 min.

Example 45:(S)-1-benzyl-4-fluoro-5-methyl-N-(4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-pyrazole-3-carboxamide

Step 1: Preparation of(3S)-3-amino-2,3,4,5-tetrahydro-1,5-benzoxazepin-4-one hydrochloride

tert-ButylN-((3S)-4-oxo-2,3,4,5-tetrahydro-1,5-benzoxazepin-3-yl)carbamate (100mg, 0.36 mmol) was added to a solution of hydrogen chloride in1,4-dioxane (4 M, 5 mL). The reaction mixture was stirred for 2 hours atroom temperature and concentrated under reduced pressure to afford thetitle compound (100 mg crude) as a white solid, which was used directlyin the next step without further purification. LC-MS (Method E):m/z=178.9 [M+H]⁺, 0.397 min.

Step 2: Preparation of(S)-1-benzyl-4-fluoro-5-methyl-N-(4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-pyrazole-3-carboxamide

The crude product obtained using Amide Coupling Procedure B was purifiedby Prep-HPLC with the following conditions: Column: XBridge Prep C18 OBDColumn 19×150 mm 5 μm; Mobile Phase A: water (10 mmol/L NH₄HCO₃), MobilePhase B: ACN; Flow rate: 30 mL/min; Gradient: 15% B to 45% B in 10 min;254 nm. The collected fractions were combined and concentrated underreduced pressure to afford the title compound. ¹H NMR (400 MHz, DMSO-d₆)δ 10.15 (s, 1H), 8.09 (d, J=7.6 Hz, 1H), 7.43-7.28 (m, 3H), 7.20-7.09(m, 6H), 5.39 (s, 2H), 4.80 (dt, J=10.0, 7.3 Hz, 1H), 4.53-4.39 (m, 2H),2.17 (d, J=1.4 Hz, 3H). LC-MS (Method F): m/z=395.0 [M+H]⁺, 2.860 min.

Example46:5-benzyl-N-((2S)-4-methyl-3-oxo-1,1a,2,3,4,8b-hexahydrobenzo[b]cyclopropa[d]azepin-2-yl)-4H-1,2,4-triazole-3-carboxamide

The crude product obtained using Amide Coupling Procedure C was purifiedby Prep-HPLC with the following conditions: Column: XBridge Prep C18 OBDColumn, 5 μm, 19×150 mm; Mobile Phase A: water (0.05% TFA), Mobile PhaseB: ACN; Flow rate: 20 mL/min; Gradient: 35% B to 65% B over 7 min;254/220 nm to afford the title compound. LC-MS (Method J): m/z=388.2[M+H]⁺, 1.305 min.

The enantiomers of5-benzyl-N-{7-methyl-6-oxo-7-azatricyclo[6.4.0.0{circumflex over( )}{circumflex over( )}{2,4}]dodeca-1(8),9,11-trien-5-yl}-4H-1,2,4-triazole-3-carboxamidewere separated by Prep-Chiral-HPLC with the following conditions:Column: CHIRALPAK IC, 2.0 cm×25 cm (5 μm); Mobile Phase A: hexanes,Mobile Phase B: EtOH; Flow rate: 20 mL/min; Gradient: 50% B to 50% Bover 30 min; 254/220 nm; RT1: 10.478 min; RT2: 13.826 min to afford thetitle compounds:

Example 46A (first eluting isomer): ¹H NMR (400 MHz, Chloroform-d) δ8.54 (d, J=7.1 Hz, 1H), 7.39-7.17 (m, 8H), 7.11 (d, J=7.5 Hz, 1H), 4.80(d, J=7.0 Hz, 1H), 4.22 (s, 2H), 3.35 (s, 3H), 2.28-1.80 (m, 2H), 1.21(m, 1H), 1.04 (m, 1H). LC-MS (Method J): m/z=388.2 [M+H]⁺, 1.302 min.

Example 46B (second eluting isomer): ¹H NMR (400 MHz, Chloroform-d) δ8.53 (d, J=7.1 Hz, 1H), 7.39-7.18 (m, 8H), 7.12 (d, J=7.7 Hz, 1H), 4.80(d, J=7.0 Hz, 1H), 4.23 (s, 2H), 3.35 (s, 3H), 2.09 (m, 1H), 2.02 (m,1H), 1.21 (m, 1H), 1.05 (m, 1H). LC-MS (Method J): m/z=388.2 [M+H]⁺,1.306 min.

Example 47:(S)-4-fluoro-5-methyl-N-(4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1-(1-phenylcyclopropyl)-1H-pyrazole-3-carboxamide

Example 48:(S)—N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-5-(3-phenyloxetan-3-yl)-4H-1,2,4-triazole-3-carboxamide

Example 49:(S)—N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-5-(phenylsulfonyl)thiazole-2-carboxamide

Step 1: Preparation of ethyl 5-(phenylthio)thiazole-2-carboxylate

To a stirring mixture of ethyl 5-iodo-1,3-thiazole-2-carboxylate (300mg, 1.06 mmol), sodium benzenethiolate (220 mg, 1.66 mmol) in1-methyl-2-pyrrolidinone (10 mL) was added cuprous iodide (40 mg, 0.21mmol) under an argon atmosphere. The resulting solution was stirred for4 hours at 70° C., quenched with water (20 mL) and extracted with ethylacetate (4×20 mL). The combined organic layers were washed with brine,dried over anhydrous sodium sulfate, filtered and concentrated undervacuum. The residue was purified by Prep-TLC (ethyl acetate/petroleumether, 5/1) to afford the title compound (120 mg, 43%) as a yellow oil.LC-MS (Method S): m/z=266.0 [M+H]⁺, 1.040 min.

Step 2: Preparation of ethyl 5-(phenylsulfonyl)thiazole-2-carboxylate

To a stirring mixture of ethyl 5-(phenylthio)thiazole-2-carboxylate (100mg, 0.38 mmol) in dichloromethane (4 mL) was added 3-chloroperoxybenzoicacid (167 mg, 0.97 mmol). The reaction mixture was stirred for 2 hoursat room temperature and concentrated under vacuum. The residue waspurified by column chromatography (ethyl acetate/petroleum ether, 1/5)to afford the title compound (100 mg, 88%) as a yellow oil. LC-MS(Method S): m/z=298.0 [M+H]⁺, 0.931 min.

Step 3: Preparation of 5-(phenylsulfonyl)thiazole-2-carboxylic acid

To a stirring mixture of ethyl 5-(phenylsulfonyl)thiazole-2-carboxylate(100 mg, 0.34 mmol) in tetrahydrofuran (3 mL) and water (1 mL) was addedlithium hydroxide (12 mg, 0.50 mmol). The resulting mixture was stirredfor 2 hours at room temperature and concentrated under vacuum. Theresidue was diluted with water (10 mL) and adjusted to pH=6 with aqueoushydrochloric acid (1 N, 10 mL). The resulting solution was extractedwith ethyl acetate (3×20 mL). The combined organic layers were washedwith brine, dried over anhydrous sodium sulfate, and filtered. Thefiltrate was concentrated under vacuum to afford the title compound (90mg crude) as a white oil, which was used directly in the next stepwithout further purification. LC-MS (Method E): m/z=270.0 [M+H]⁺, 0.635min.

Step 4: Preparation of(S)—N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-5-(phenylsulfonyl)thiazole-2-carboxamide

The crude product obtained using Amide Coupling Procedure B was purifiedby Prep-HPLC with the following conditions: column: Xbridge Prep C18,19×150 mm, 5 μm; Mobile phase: Phase A: water (10 mmol/L NH₄HCO₃); PhaseB: ACN (20% to 80% over 12 min); Detector, UV 220 & 254 nm to afford thetitle compound. ¹H NMR (300 MHz, DMSO-d₆) δ 9.24 (br. s, 1H), 8.76 (s,1H), 8.10-8.01 (m, 2H), 7.82-7.63 (m, 3H), 7.52-7.44 (m, 1H), 7.38-7.17(m, 3H), 4.83-4.70 (m, 1H), 4.71-4.59 (m, 1H), 4.45-4.32 (m, 1H), 3.30(s, 3H). LC-MS (Method O): m/z=443.9 [M+H]⁺, 1.594 min.

Example 50:(1R,2S)-2-benzyl-N—((S)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)cyclopropane-1-carboxamide

Step 1: Preparation of (±)-trans-2-benzylcyclopropanecarboxylic acid

Sodium hydroxide (60%, 74 mg, 1.84 mmol) was added to a solution of(±)-trans-ethyl 2-benzylcyclopropanecarboxylate (200 mg, 0.74 mmol) inmethanol (12 mL) and water (6 mL). The reaction mixture was stirredovernight at room temperature. After removal of methanol under reducedpressure, the pH value of the solution was adjusted to 6 with aqueoushydrochloric acid (1 N, 10 mL). The resulting mixture was extracted withethyl acetate (3×10 mL). The combined organic layers were washed withbrine, dried over anhydrous sodium sulfate, filtered and concentratedunder vacuum to afford the title compound (95 mg, 73%) as a yellow oil.LC-MS (Method I): m/z=177.0 [M+H]⁺, 0.877 min.

Step 2: Preparation oftrans-2-benzyl-N—((S)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)cyclopropanecarboxamide

The crude product obtained using Amide Coupling Procedure C was purifiedby Prep-HPLC with the following conditions: Column, Xbridge Prep C18 OBDColumn, 5 μm, 19×150 mm; mobile phase, water (10 mmol/L NH₄HCO₃) and ACN(40.0% ACN to 65.0% over 8 min); Detector, UV 254 nm to afford the titlecompound. LC-MS (Method J): m/z=351.1 [M+H]⁺, 2.116 min.

Step 3: Preparation of(R,2S)-2-benzyl-N—((S)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)cyclopropanecarboxamideand(S,2R)-2-benzyl-N—((S)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)cyclopropanecarboxamide

The diastereomers of trans2-benzyl-N—((S)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)cyclopropanecarboxamidewere separated by Prep-Chiral-HPLC with the following conditions:Column: Phenomenex Lux Cellulose-4, AXIA Packed, 2.12×25 cm, 5 μm;Mobile Phase A: hexanes, Mobile Phase B: EtOH; Flow rate: 20 mL/min;Gradient: 30% B to 30% B over 12 min; 254/220 nm; RT1: 7.474 min; RT2:8.916 min to afford the title compounds:

Example 50A (first eluting isomer): ¹H NMR (400 MHz, Chloroform-d) δ7.31-7.23 (m, 2H), 7.24-7.11 (m, 7H), 6.65 (d, J=6.4 Hz, 1H), 4.94-4.85(m, 1H), 4.69-4.61 (m, 1H), 4.18-4.09 (m, 1H), 3.44 (s, 3H), 2.79-2.71(m, 1H), 2.58-2.50 (m, 1H), 1.57 (s, 1H), 1.37-1.33 (m, 1H), 1.20-1.16(m, 1H), 0.80-0.75 (m, 1H). LC-MS (Method J): m/z=351.1 [M+H]⁺, 2.116min.

Example 50B (second eluting isomer): ¹H NMR (400 MHz, Chloroform-d) δ7.31-7.26 (m, 2H), 7.21-7.13 (m, 7H), 6.59 (d, J=6.4 Hz, 1H), 4.95-4.84(m, 1H), 4.69-4.58 (m, 1H), 4.16-4.09 (m, 1H), 3.43 (s, 3H), 2.79-2.70(m, 1H), 2.63-2.54 (m, 1H), 1.67-1.57 (m, 1H), 1.37-1.32 (m, 1H),1.17-1.13 (m, 1H), 0.78-0.73 (m, 1H). LC-MS (Method J): m/z=351.1[M+H]⁺, 1.451 min.

Example 51:5-(2,3-dihydro-1H-inden-1-yl)-N—((S)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4H-1,2,4-triazole-3-carboxamide

Step 1: Preparation of 2,3-dihydro-1H-indene-1-carbohydrazide

A solution of hydrazine in tetrahydrofuran (1 M, 31 mL, 31 mmol) wasadded to a solution of 2,3-dihydro-1H-indene-1-carboxylic acid (1.0 g,6.2 mmol), 2-(7-aza-1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluroniumhexafluorophosphate (2.8 g, 7.4 mmol) and ethyldiisopropylamine (2.4 g,18.6 mmol) in N,N-dimethylformamide (20 mL). After stirring for 1 hourat room temperature, the reaction mixture was diluted with water (20 mL)and extracted with ethyl acetate (3×50 mL). The combined organic layerswere washed with brine, dried over anhydrous sodium sulfate, filteredand concentrated under vacuum. The residue was purified by columnchromatography (methanol/dichloromethane, 1/10) to afford the titlecompound (0.87 g, 80%) as a white solid. LC-MS (Method E): m/z=177.0[M+H]⁺, 0.506 min.

Step 2: Preparation of ethyl2-amino-2-(2-(2,3-dihydro-1H-indene-1-carbonyl)hydrazono)acetate

Ethyl 2-ethoxy-2-iminoacetate (412 mg, 2.8 mmol) was added to a solutionof 2,3-dihydro-1H-indene-1-carbohydrazide (500 mg, 2.8 mmol) in ethanol(5 mL) and diethyl ether (5 mL). The resulting suspension was stirred atroom temperature for 2 hours. The solids were removed by filtration andthe filtrate was concentrated under vacuum to afford the title compound(600 mg, 78%) as a yellow solid. LC-MS (Method S): m/z=276.2 [M+H]⁺,0.709 min.

Step 3: Preparation of ethyl5-(2,3-dihydro-1H-inden-1-yl)-4H-1,2,4-triazole-3-carboxylate

Ethyl 2-amino-2-(2-(2,3-dihydro-1H-indene-1-carbonyl)hydrazono)acetate(600 mg, 2.2 mmol) was added to xylene (10 mL) in a sealed tube. Thereaction mixture was heated for 5 hours at 170° C. irradiated bymicrowave. After concentration under high vacuum, the residue waspurified by column chromatography (methanol/dichloromethane, 1/10) toafford the title compound (340 mg, 60%) as a yellow oil. LC-MS (MethodI): m/z=258.1 [M+H]⁺, 0.848 min.

Step 4: Preparation of5-(2,3-dihydro-1H-inden-1-yl)-4H-1,2,4-triazole-3-carboxylic acid

Lithium hydroxide (95.3 mg, 4.0 mmol) was added to a solution of ethyl5-(2,3-dihydro-1H-inden-1-yl)-4H-1,2,4-triazole-3-carboxylate (340 mg,1.3 mmol) in tetrahydrofuran (6 mL) and water (3 mL). After stirring atroom temperature for 4 hours and removing tetrahydrofuran under reducedpressure, the reaction mixture was diluted with water (20 mL), the pHwas adjusted to 2 with aqueous hydrochloric acid (1 N, 20 mL), andextracted with ethyl acetate (3×50 mL). The combined organic layers werewashed with brine, dried over anhydrous sodium sulfate, filtered andconcentrated under vacuum to afford the title compound (140 mg, 47%) asa yellow solid. LC-MS (Method E): m/z=229.9 [M+H]⁺, 0.642 min.

Step 5: Preparation of5-(2,3-dihydro-1H-inden-1-yl)-N—((S)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4H-1,2,4-triazole-3-carboxamide

The crude product obtained using Amide Coupling Procedure B was purifiedby Prep-HPLC with the following conditions: Column: XBridge Shield RP18OBD Column, 5 μm, 19×150 mm; Mobile Phase A: water (10 mmol/L NH₄HCO₃),Mobile Phase B: ACN; Flow rate: 20 mL/min; Gradient: 25% B to 50% B over10 min; 254 nm to afford the title compound. ¹H NMR (400 MHz,Chloroform-d) δ 8.12 (d, J=7.2 Hz, 1H), 7.33 (d, J=7.2, 1H), 7.29-7.19(m, 6H), 5.17-5.06 (m, 1H), 4.77-4.67 (m, 2H), 4.34-4.27 (m, 1H), 3.45(s, 3H), 3.16-3.01 (m, 2H), 2.68-2.63 (m, 1H), 2.46-2.39 (m, 1H). LC-MS(Method J): m/z=404.3 [M+H]⁺, 1.332 min.

Example 52:(S)-5-benzyl-N-(5,6-dihydro-4H-benzo[f]imidazo[1,2-a]azepin-4-yl)-4H-1,2,4-triazole-3-carboxamide

The crude product obtained using Amide Coupling Procedure C was purifiedby Prep-HPLC with the following conditions: Column, XBridge Shield RP18OBD Column, 5 μm, 19×150 mm; mobile phase, water (0.05% TFA) and ACN(10.0% ACN to 40.0% over 7 min); Detector, UV 220 & 254 nm to afford thetitle compound. ¹H NMR (300 MHz, DMSO-d₆) δ 14.43 (s, 1H), 8.67 (s, 1H),7.56 (d, J=1.5 Hz, 1H), 7.53-7.47 (m, 3H), 7.46-7.22 (m, 6H), 7.04 (d,J=1.5 Hz, 1H), 4.87-4.77 (m, 1H), 4.14 (s, 2H), 2.80-2.73 (m, 1H),2.67-2.56 (m, 1H), 2.46-2.32 (m, 2H). LC-MS (Method O): m/z=385.0[M+H]⁺, 1.229 min.

Example 53:3-benzyl-N-(8-bromo-1-methyl-2-oxo-2,3,4,5-tetrahydro-1H-pyrrolo[1,2-a][1,3]diazepin-3-yl)-1H-1,2,4-triazole-5-carboxamide

Example 54A and 54B:5-((R)-2,3-dihydro-1H-inden-1-yl)-N—((S)-5-methyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepin-3-yl)-4H-1,2,4-triazole-3-carboxamideand5-((S)-2,3-dihydro-1H-inden-1-yl)-N—((S)-5-methyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepin-3-yl)-4H-1,2,4-triazole-3-carboxamide

Step 1: Preparation of5-(2,3-dihydro-1H-inden-1-yl)-N—((S)-5-methyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepin-3-yl)-4H-1,2,4-triazole-3-carboxamide

A solution of trimethylaluminum in toluene (2 M, 0.6 mL, 1.2 mmol) wasadded to a mixture of(S)-3-amino-5-methyl-2,3-dihydropyrido[3,2-b][1,4]oxazepin-4(5H)-onehydrochloride (60 mg, 0.26 mmol) in toluene (2 mL) dropwise at 0° C. Theresulting solution was warmed to room temperature and stirred for 30minutes. A solution of ethyl5-(2,3-dihydro-1H-inden-1-yl)-4H-1,2,4-triazole-3-carboxylate (108 mg,0.42 mmol) in toluene (2 mL) was added to the resulting solutiondropwise. The resulting solution was stirred overnight at roomtemperature. The solution was then quenched with water (10 mL) andextracted with ethyl acetate (3×50 mL). The organic layers were combinedand concentrated under vacuum. The residue was purified by Prep-HPLCwith the following conditions: Column: XBridge Prep Phenyl OBD Column19×150 mm, 5 mm; Mobile Phase A: water (0.05% NH₃H₂O), Mobile Phase B:ACN; Flow rate: 20 mL/min; Gradient: 25% B to 50% B over 7 min; 254 nm;Rt: 6 min to afford the title compound (25 mg, 23.8%) as a white solid.LC-MS (Method D): m/z=405.1 [M+H]⁺, 1.759 min.

Step 2: Preparation of5-((R)-2,3-dihydro-1H-inden-1-yl)-N—((S)-5-methyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepin-3-yl)-4H-1,2,4-triazole-3-carboxamideand5-((S)-2,3-dihydro-1H-inden-1-yl)-N—((S)-5-methyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepin-3-yl)-4H-1,2,4-triazole-3-carboxamide

5-(2,3-dihydro-1H-inden-1-yl)-N—((S)-5-methyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepin-3-yl)-4H-1,2,4-triazole-3-carboxamide(25 mg) was separated by Prep-Chiral-HPLC with the following conditions:Column: Chiralpak IA, 2×25 cm, 5 μm; Mobile Phase A: hexane, MobilePhase B: EtOH; Flow rate: 16 mL/min; Gradient: 50% B to 50% B over 40min; 220/254 nm; RT1: 9.716 min; RT2: 29.084 min to afford the titlecompounds:

54A (first eluting isomer): ¹H NMR (400 MHz, Methanol-d₄) δ 8.36-8.35(m, 1H), 7.70-7.68 (m, 1H), 7.34-7.31 (m, 2H), 7.25-7.24 (m, 1H),7.22-7.19 (m, 1H), 7.16-7.07 (m, 1H), 5.07-5.02 (m, 1H), 4.72-4.65 (m,2H), 4.55-4.50 (m, 1H), 3.49 (s, 3H), 3.18-3.15 (m, 1H), 3.07-3.05 (m,1H), 2.65-2.62 (m, 1H), 2.43-2.38 (m, 1H). LC-MS (Method T): m/z=405.3[M+H]⁺, 1.296 min.

54B (second eluting isomer): ¹H NMR (400 MHz, Methanol-d₄) δ 8.36-8.35(m, 1H), 7.70-7.68 (m, 1H), 7.34-7.31 (m, 2H), 7.25-7.24 (m, 1H),7.22-7.19 (m, 1H), 7.16-7.07 (m, 1H), 5.07-5.02 (m, 1H), 4.72-4.65 (m,2H), 4.55-4.50 (m, 1H), 3.49 (s, 3H), 3.18-3.15 (m, 1H), 3.07-3.05 (m,1H), 2.65-2.62 (m, 1H), 2.43-2.38 (m, 1H). LC-MS (Method T): m/z=405.3[M+H]⁺, 1.301 min.

Example 55:(S)-4-fluoro-N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1-(pyridin-2-ylmethyl)-1H-pyrazole-3-carboxamide

Step 1: Preparation of ethyl 4-fluoro-1H-pyrazole-3-carboxylate

1-(Chloromethyl)-4-fluoro-1,4-diazonia-bicyclo[2.2.2]octanetetrafluoroborate (14 g, 39.5 mmol) was added to a mixture of ethyl1H-pyrazole-3-carboxylate (5 g, 35.7 mmol) in acetonitrile (50 mL). Theresulting mixture was stirred for 48 hours at 100° C. After cooling toroom temperature, the solids were removed by filtration and the filtratewas concentrated under vacuum to afford the title compound (2.4 g) as ayellow solid. LC-MS (Method S): m/z=159.2 [M+H]⁺, 0.639 min.

Step 2: Preparation of4-fluoro-1-(pyridin-2-ylmethyl)-1H-pyrazole-3-carboxylic acid

Sodium hydride (60%, 506 mg, 12.7 mmol) was added to a solution of ethyl4-fluoro-1H-pyrazole-3-carboxylate (500 mg, 3.2 mmol) inN,N-dimethylformamide (10 mL) at 0° C. The resulting mixture was stirredat room temperature for 0.5 hour before adding 2-(bromomethyl)pyridine(600 mg, 3.5 mmol). The reaction mixture was stirred at room temperaturefor 1.5 hours and quenched by adding water (10 mL). The resultingsolution was stirred at room temperature for 5 hours. The pH wasadjusted to 7 with aqueous hydrochloric acid (1 N, 10 mL). The resultingsolution was extracted with ethyl acetate (3×50 mL). The combinedorganic layers were washed with brine, dried over anhydrous sodiumsulfate, filtered and concentrated under vacuum to afford the titlecompound (360 mg, 72%). LC-MS (Method I): m/z=221.9 [M+H]⁺, 0.320 min.

Step 3: Preparation of(S)-4-fluoro-N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1-(pyridin-2-ylmethyl)-1H-pyrazole-3-carboxamide

The crude product obtained using Amide Coupling Procedure C was purifiedby Prep-HPLC with the following conditions: Column: XBridge Prep C18 OBDColumn, 5 μm, 19×150 mm; Mobile Phase A: water (10 mmol/L NH₄HCO₃),Mobile Phase B: ACN; Flow rate: 20 mL/min; Gradient: 30% B to 45% B over7 min; 254/220 nm to afford the title compound. ¹H NMR (400 MHz,DMSO-d₆) δ 8.56-8.55 (m, 1H), 8.16-8.15 (d, J=4.4 Hz, 1H), 8.11-8.09 (m,1H), 7.83-7.82 (m, 1H), 7.51-7.49 (m, 1H), 7.34-7.28 (m, 3H), 7.24-7.20(m, 2H), 5.46 (s, 2H), 4.91-4.78 (m, 1H), 4.58-4.53 (m, 1H), 4.41-4.37(m, 1H), 3.33 (s, 3H). LC-MS (Method F): m/z=396.1 [M+H]⁺, 0.924 min.

Example 56:(S)-5-benzyl-N-(9-cyano-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-2H-1,2,4-triazole-3-carboxamide

Step 1: (S)-tert-butyl9-cyano-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-ylcarbamate

To a mixture of (S)-tert-butyl9-chloro-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-ylcarbamate(200 mg, 0.61 mmol) and zinc cyanide (300 mg, 2.59 mmol) intetrahydrofuran (2 mL) and water (10 mL) were added 3rd generationt-BuXPhos precatalyst (244 mg, 0.31 mmol) and t-BuXPhos (130 mg, 0.31mmol) under a nitrogen atmosphere. The reaction mixture was stirredovernight at room temperature and diluted with water (50 mL). Theresulting mixture was extracted with ethyl acetate (3×50 mL). Thecombined organic layers were washed with brine, dried over anhydroussodium sulfate, filtered and concentrated under vacuum. The residue waspurified by column chromatography (ethyl acetate/petroleum ether, 1/6)to afford the title compound (150 mg, 78%) as a white solid. LC-MS(Method E): m/z=262.0 [M+H-56]⁺, 0.853 min.

Step 2: Preparation of(S)-3-amino-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-9-carbonitrilehydrochloride

A solution of hydrogen chloride in 1,4-dioxane (4 N, 10 mL) was added toa solution of (S)-tert-butyl9-cyano-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-ylcarbamate(90 mg, 0.28 mmol) in 1,4-dioxane (2 mL). The reaction mixture wasstirred for 1 hour at room temperature and concentrated under vacuum toafford the title compound (55 mg) as a white solid. LC-MS (Method E):m/z=218.0 [M+H]⁺, 0.551 min.

Step 3: Preparation of(S)-5-benzyl-N-(9-cyano-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4H-1,2,4-triazole-3-carboxamide

The crude product obtained using Amide Coupling Procedure C was purifiedby Prep-HPLC with the following conditions: Column, Xbridge Phenyl OBDColumn, 5 μm, 19×150 mm; mobile phase, water (10 mmol/L NH₄HCO₃) and ACN(50.0% ACN to 70.0% over 7 min); Detector, UV 254 & 220 nm to afford thetitle compound. ¹H NMR (400 MHz, DMSO-d₆) δ 14.20 (s, 1H), 8.55 (s, 1H),7.81 (dd, J=8.2, 1.5 Hz, 1H), 7.72 (dd, J=7.8, 1.5 Hz, 1H), 7.44 (t,J=8.0 Hz, 1H), 7.35-7.14 (m, 5H), 4.94-4.74 (m, 2H), 4.58-4.47 (m, 1H),4.10 (s, 2H), 3.30 (s, 3H). LC-MS (Method F): m/z=403.0 [M+H]⁺, 1.069min.

Example 57:(S)-1-benzyl-4-fluoro-N-(4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepin-3-yl)-1H-pyrazole-3-carboxamide

The crude product obtained using Amide Coupling Procedure C was purifiedby Prep-HPLC with the following conditions: Column: X Bridge Shield RP18OBD Column, 5 μm, 19×150 mm; Mobile Phase A: water (0.1% formic acid),Mobile Phase B: ACN; Flow rate: 20 mL/min; Gradient: 25% B to 60% B over7 min; UV 254 & 220 nm to afford the title compound. ¹H NMR (400 MHz,DMSO-d₆) δ 10.55 (s, 1H), 8.23 (d, J=7.6 Hz, 1H), 8.17-8.13 (m, 2H),7.56 (dd, J=7.6, 1.2 Hz, 1H), 7.41-7.31 (m, 3H), 7.30-7.27 (m, 2H),7.19-7.15 (m, 1H), 5.35 (s, 2H), 4.83-4.77 (m, 1H), 4.53-4.42 (m, 2H).LC-MS (Method V): m/z=382.1 [M+H]⁺, 2.321 min.

Example 58:(S)—N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-5-(1-phenylcyclopropyl)-1,3,4-thiadiazole-2-carboxamide

Step 1: Preparation of 5-(1-phenylcyclopropyl)-1,3,4-thiadiazol-2-amine

A mixture of 1-phenylcyclopropanecarboxylic acid (1.6 g, 10 mmol) andN-aminothiourea (0.91 g, 10 mmol) in phosphoryl trichloride (10 mL) washeated for 1 hour at 70° C. and then cooled to room temperature. Water(100 mL) was added. The reaction mixture was heated to 70° C. andstirred for 5 hours. The pH value of the resulting solution was adjustedto 8 with saturated aqueous sodium hydroxide (30 mL). The solids werecollected by filtration to afford the title compound (1.9 g, 87%) as awhite solid. LC-MS (Method Q): m/z=218.1 [M+H]⁺, 0.817 min.

Step 2: Preparation of 2-bromo-5-(1-phenylcyclopropyl)-1,3,4-thiadiazole

To a mixture of 5-(1-phenylcyclopropyl)-1,3,4-thiadiazol-2-amine (1.1 g,5.0 mmol) in acetonitrile (20 mL) was added cupric bromide (2.2 g, 10mmol). The resulting mixture was stirred at room temperature for 15minutes before adding tert-butyl nitrite (1.5 mL, 10 mmol) to themixture dropwise over a period of 15 minutes at room temperature. Thereaction mixture was heated at 60° C. and stirred for 16 hours beforeadding water (50 mL). The solids were removed by filtration and thefiltrate was extracted with ethyl acetate (3×50 mL). The combinedorganic layers were washed with brine, dried over anhydrous sodiumsulfate, filtered and concentrated under vacuum. The residue waspurified by column chromatography (ethyl acetate/petroleum ether, 1/10)to afford the title compound (1.0 g, 70%) as a yellow solid. LC-MS(Method K): m/z=281.0 [M+H]⁺, 1.107 min.

Step 3: Preparation of ethyl5-(1-phenylcyclopropyl)-1,3,4-thiadiazole-2-carboxylate

Bis(triphenylphosphine)palladium(II) chloride (277 mg, 0.395 mmol) wasadded to a mixture of 2-bromo-5-(1-phenylcyclopropyl)-1,3,4-thiadiazole(1.0 g, 3.57 mmol) and triethylamine (879 mg, 8.70 mmol) in methanol (20mL). After stirring for 16 hours at 100° C. under a carbon monoxideatmosphere (50 atm), the reaction mixture was diluted with water (20 mL)and extracted with ethyl acetate (3×20 mL). The combined organic layerswere washed with brine, dried over anhydrous sodium sulfate, filteredand concentrated under vacuum. The residue was purified by columnchromatography (ethyl acetate/petroleum ether, 1/20) to afford the titlecompound (600 mg, 61%) as a yellow solid. LC-MS (Method E): m/z=261.1[M+H]⁺, 0.923 min.

Step 4: Preparation of5-(1-phenylcyclopropyl)-1,3,4-thiadiazole-2-carboxylic acid

Lithium hydroxide (5.4 mg, 2.0 mmol) was added to a solution of ethyl5-(1-phenylcyclopropyl)-1,3,4-thiadiazole-2-carboxylate (100 mg, 0.41mmol) in tetrahydrofuran (9 mL) and water (3 mL). The resulting mixturewas stirred for 2 hours at room temperature. After removal oftetrahydrofuran under reduced pressure, the pH value of the solution wasadjusted to 3-4 with aqueous hydrochloric acid (1 N, 20 mL). Theresulting mixture was extracted with ethyl acetate (3×10 mL). Thecombined organic layers were washed with brine, dried over anhydroussodium sulfate, filtered and concentrated under vacuum to afford thetitle compound (80 mg, 76%) as a yellow oil. LC-MS (Method C): m/z=247.0[M+H]⁺, 1.288 min.

Step 5: Preparation of(S)—N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-5-(1-phenylcyclopropyl)-1,3,4-thiadiazole-2-carboxamide

The crude product obtained using Amide Coupling Procedure C was purifiedby Prep-HPLC with the following conditions: column: Xbridge Prep C18,19×150 mm 5 μm; Mobile phase: water (10 mmol/L NH₄HCO₃) and ACN (20% to80% over 12 min); Detector, UV220 & 254 nm to afford the title compound.¹H NMR (300 MHz, DMSO-d₆) δ 9.20 (s, 1H), 7.49-7.18 (m, 9H), 4.77-4.75(m, 1H), 4.69-4.62 (m, 1H), 4.41-4.35 (m, 1H), 3.27 (s, 3H), 1.82-1.76(m, 2H), 1.66-1.57 (m, 2H). LC-MS (Method V): m/z=421.1 [M+H]⁺, 3.918min.

Example 59:5-benzyl-N-[(3S)-1-methyl-2-oxo-1,2,3,4-tetrahydrospiro[1-benzazepine-5,1-cyclopropane]-3-yl]-1H-pyrazole-3-carboxamide

The crude product obtained using Amide Coupling Procedure C was purifiedby Prep-HPLC with the following conditions: Column, Xbridge Phenyl OBDColumn, 5 μm, 19×150 mm; mobile phase, water (10 mmol/L NH₄HCO₃) and ACN(50.0% ACN to 70.0% over 7 min); Detector, UV 254 & 220 nm to afford thetitle compound. ¹H NMR (300 MHz, DMSO-d₆) δ 13.15 (s, 1H), 7.88 (d,J=8.1 Hz, 1H), 7.45-7.36 (m, 2H), 7.35-7.18 (m, 7H), 6.34 (s, 1H),4.46-4.36 (m, 1H), 3.97 (s, 2H), 3.29 (s, 3H), 2.72-2.64 (m, 1H), 1.51(t, J=12.0 Hz, 1H), 1.10-1.04 (m, 1H), 0.74-0.66 (m, 2H), 0.43-0.37 (m,1H). LC-MS (Method D): m/z=401.2 [M+H]⁺, 1.994 min.

Examples 60A and 60B:5-benzyl-N-((1aS,2S,8bR)-4-methyl-3-oxo-1,1a,2,3,4,8b-hexahydrobenzo[b]cyclopropa[d]azepin-2-yl)-1H-pyrazole-3-carboxamide(60A) and5-benzyl-N-((1aR,2R,8bS)-4-methyl-3-oxo-1,1a,2,3,4,8b-hexahydrobenzo[b]cyclopropa[d]azepin-2-yl)-1H-pyrazole-3-carboxamide(60B)

Step 1: Preparation of5-benzyl-N-(4-methy-3-oxo-1,1a,2,3,4,8b-hexahydrobenzo[b]cyclopropa[d]azepin-2-yl)-1H-pyrazole-3-carboxamide

The crude product obtained using Amide Coupling Procedure C was purifiedby Prep-HPLC with the following conditions: Column: XBridge Prep C18 OBDColumn, 5 μm, 19×150 mm; Mobile Phase A: water (0.05% TFA), Mobile PhaseB: ACN; Flow rate: 20 mL/min; Gradient: 35% B to 65% B over 7 min;254/220 nm to afford the title compound. LC-MS (Method I): m/z=387.2[M+H]⁺, 1.405 min.

Step 2: Preparation of5-benzyl-N-((1aS,2S,8bR)-4-methyl-3-oxo-1,1a,2,3,4,8b-hexahydrobenzo[b]cyclopropa[d]azepin-2-yl)-1H-pyrazole-3-carboxamide(First Eluting Isomer) and5-benzyl-N-((1aR,2R,8bS)-4-methyl-3-oxo-1,1a,2,3,4,8b-hexahydrobenzo[b]cyclopropa[d]azepin-2-yl)-1H-pyrazole-3-carboxamide(Second Eluting Isomer)

5-Benzyl-N-{7-methyl-6-oxo-7-azatricyclo[6.4.0.0{circumflex over( )}{2,4}]dodeca-1(8),9,11-trien-5-yl}-1H-pyrazole-3-carboxamide (30 mg,0.077 mmol) was separated by Prep-Chiral-HPLC with the followingconditions: Column: CHIRALPAK IC, 2.0 cm×25 cm (5 μm); Mobile Phase A:hexanes, Mobile Phase B: EtOH; Flow rate: 20 mL/min; Gradient: 50% B to50% B over 30 min; 254/220 nm; RT1: 10.478 min; RT2: 13.826 min toafford the title compounds:

Example 60A (first eluting isomer): ¹H NMR (300 MHz, Chloroform-d) δ8.47 (d, J=7.7 Hz, 1H), 7.41-7.08 (m, 9H), 6.57 (s, 1H), 4.85 (d, J=7.6Hz, 1H), 4.04 (s, 2H), 3.32 (s, 3H), 2.18-1.92 (m, 2H), 1.16-0.88 (m,2H). LC-MS (Method J): m/z=387.2 [M+H]⁺, 2.043 min.

Example 60B (second eluting isomer): ¹H NMR (300 MHz, Chloroform-d) δ8.29 (s, 1H), 7.39-7.05 (m, 9H), 6.53 (s, 1H), 4.85 (d, J=7.6 Hz, 1H),4.04 (s, 2H), 3.31 (s, 3H), 2.18-1.92 (m, 2H), 1.16-1.07 (m, 1H),1.02-0.89 (m, 1H). LC-MS (Method J): m/z=387.2 [M+H]⁺, 1.409 min.

Example 61:(S)—N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-2-(1-phenylcyclopropyl)oxazole-4-carboxamide

Step 1: Preparation of 1-phenylcyclopropanecarboxamide

To a stirring solution of 1-phenylcyclopropanecarboxylic acid (1.62 g,10.0 mmol) in dichloromethane (10 mL) was added thionyl chloride (6 g,50.0 mmol) dropwise at 0° C. The resulting solution was stirred for 5hours at room temperature and the reaction mixture was concentratedunder high vacuum. The residue was then added to ammonium hydroxide(28%, 50 mL) dropwise at 0° C. The resulting solution was diluted withwater (50 mL) and extracted with ethyl acetate (3×100 mL). The combinedorganic layers were washed with brine, dried over anhydrous sodiumsulfate, filtered and concentrated under vacuum to afford the titlecompound (1.50 g, 93%) as a yellow solid. LC-MS (Method I): m/z=162.1[M+H]⁺, 0.725 min.

Step 2: Preparation of ethyl2-(1-phenylcyclopropyl)oxazole-4-carboxylate

A mixture of ethyl 3-bromo-2-oxopropanoate (970 mg, 5.0 mmol) and1-phenylcyclo-propanecarboxamide (810 mg, 5.0 mmol) in ethanol (10 mL)was heated for 16 hours at 80° C. under a nitrogen atmosphere. Aftercooling to room temperature, the reaction mixture was quenched by theaddition of water (50 mL) and extracted with ethyl acetate (3×50 mL).The combined organic layers were washed with saturated aqueous sodiumcarbonate (30 mL) and brine (30 mL), dried over anhydrous sodiumsulfate, filtered and concentrated under vacuum. The residue waspurified by column chromatography (ethyl acetate/petroleum ether, 1/10)to afford the title compound (420 mg, 33%) as a white solid. LC-MS(Method C): m/z=258.1 [M+H]⁺, 1.527 min.

Step 3: Preparation of 2-(1-phenylcyclopropyl)oxazole-4-carboxylic acid

Lithium hydroxide (5.4 mg, 2.02 mmol) was added to a mixture of ethyl2-(1-phenylcyclopropyl) oxazole-4-carboxylate (100 mg, 0.39 mmol) intetrahydrofuran (9 mL) and water (3 mL). The reaction mixture wasstirred for 16 hours at room temperature. After removal oftetrahydrofuran under reduced pressure, the pH value of the solution wasadjusted to 6 with aqueous hydrochloric acid (1 N, 5 mL). The resultingmixture was extracted with ethyl acetate (3×10 mL). The combined organiclayers were washed with brine, dried over anhydrous sodium sulfate,filtered and concentrated under vacuum to afford the title compound (67mg, 76%) as a yellow oil. LC-MS (Method C): m/z=230.1 [M+H]⁺, 1.291 min.

Step 4: Preparation of(S)—N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-2-(1-phenylcyclopropyl)oxazole-4-carboxamide

The crude product obtained using Amide Coupling Procedure C was purifiedby Prep-HPLC with the following conditions: column: Xbridge Prep C18,19×150 mm, 5 μm; Mobile phase: Phase A: water (10 mmol/L NH₄HCO₃); PhaseB: ACN (20% to 80% over 12 min); Detector, UV220 & 254 nm to afford thetitle compound. ¹H NMR (300 MHz, DMSO-d₆) δ 8.45 (s, 1H), 8.11 (d, J=7.8Hz, 1H), 7.49-7.19 (m, 9H), 4.85-4.76 (m, 1H), 4.57-4.50 (m, 1H),4.39-4.33 (m, 1H), 3.29 (s, 3H), 1.61-1.58 (m, 2H), 1.42-1.38 (m, 2H).LC-MS (Method D): m/z=404.2 [M+H]⁺, 2.148 min.

Example 62:(S)—N-(4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepin-3-yl)-5-(1-phenylcyclopropyl)isoxazole-3-carboxamide

The crude product obtained using Amide Coupling Procedure C was purifiedby Prep-HPLC with the following conditions: Column: X Select CSH PrepC18 OBD Column, 5 μm, 19×150 mm; Mobile Phase A: water (0.05% TFA),Mobile Phase B: ACN; Flow rate: 20 mL/min; Gradient: 35% B to 70% B over7 min; UV 254 & 220 nm to afford the title compound. ¹H NMR (400 MHz,DMSO-d₆) δ 10.54 (s, 1H), 8.93 (d, J=8.0 Hz, 1H), 8.15 (dd, J=4.4, 1.2Hz, 1H), 7.55 (dd, J=8.0, 1.2 Hz, 1H), 7.41-7.29 (m, 5H), 7.17 (dd,J=8.0, 4.8 Hz, 1H), 6.41 (s, 1H), 4.85-4.78 (m, 1H), 4.53-4.42 (m, 2H),1.58-1.43 (m, 4H). LC-MS (Method D): m/z=391.1 [M+H]⁺, 1.981 min.

Example 63:(S)—N-(5-methyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepin-3-yl)-5-(1-phenylcyclopropyl)thiazole-2-carboxamide

Step 1: Preparation of (1-phenylcyclopropyl)methanol

A solution of borane in tetrahydrofuran (1 M, 60 mL, 60 mmol) was slowlyadded to a solution of 1-phenylcyclopropanecarboxylic acid (6.5 g, 40mmol) in tetrahydrofuran (40 mL) at 0° C. The reaction mixture wasstirred for 2 hours at room temperature, quenched with water (50 mL) andextracted with ethyl acetate (3×60 mL). The combined organic layers werewashed with brine, dried over anhydrous sodium sulfate, filtered andconcentrated under vacuum to afford the title compound (5.5 g, 93%) as acolorless oil. LC-MS (Method C): m/z=131.2 [M−H₂O+H]⁺, 1.125 min.

Step 2: Preparation of 1-phenylcyclopropanecarbaldehyde

Dess-Martin periodinane (35.6 g, 84 mmol) was added to a solution of(1-phenylcyclopropyl)methanol (5.4 g, 42 mmol) in dichloromethane (40mL) at 0° C. The resulting mixture was stirred at 0° C. for 1.5 hours.The solids were removed by filtration and the filtrate was concentratedunder vacuum. The resulting residue was purified by columnchromatography (ethyl acetate/petroleum ether, 1/10) to afford the titlecompound (4.4 g, 72%) as a colorless oil. LC-MS (Method C): m/z=147.2[M+H]⁺, 1.215 min.

Step 3: Preparation of (E)-(1-(2-methoxyvinyl)cyclopropyl)benzene

To a solution of methoxymethyl)triphenylphosphonium chloride (22.4 g, 65mmol) in tetrahydrofuran (30 mL) was added a solution of potassium2-methylpropan-2-olate in tetrahydrofuran (1 M, 65 mL, 65 mmol) at 0° C.The resulting mixture was stirred at 0° C. for 0.5 hour followed by theaddition of 1-phenylcyclopropanecarbaldehyde (4.2 g, 29 mmol). Thereaction mixture was stirred at room temperature for 1 hour, quenched bythe addition of water (100 mL) and extracted with ethyl acetate (3×100mL). The combined organic phases were washed with brine, dried overanhydrous sodium sulfate, filtered and concentrated under reducedpressure to afford the title compound (20 g crude) as a yellow oil,which was used directly in the next step without further purification.

Step 4: Preparation of 2-bromo-2-(1-phenylcyclopropyl)acetaldehyde

To a solution of (E)-(1-(2-methoxyvinyl)cyclopropyl)benzene (3.8 g, 22mmol) in tetrahydrofuran (20 mL) and water (2 mL) was addedN-bromosuccinimide (4.3 g, 24 mmol) at −20° C. The solution was stirredat −20° C. for 1 hour and concentrated to afford the title compound (8 gcrude) as a yellow oil, which was used directly in the next step withoutfurther purification.

Step 5: Preparation of ethyl5-(1-phenylcyclopropyl)thiazole-2-carboxylate

To a solution of 2-bromo-2-(1-phenylcyclopropyl)acetaldehyde (2 g, 8mmol) in ethanol (20 mL) was added ethyl 2-amino-2-thioxoacetate (1.1 g,8 mmol). The reaction mixture was stirred at 80° C. for 4 hours andconcentrated under vacuum. The residue was purified by columnchromatography (ethyl acetate/petroleum ether, 1/5) to afford the titlecompound (310 mg, 14%) as a yellow oil. LC-MS (Method I): m/z=274.0[M+H]⁺, 1.034 min.

Step 6: Preparation of 5-(1-phenylcyclopropyl)thiazole-2-carboxylic acid

Lithium hydroxide (52.8 mg, 2.2 mmol) was added to a solution of ethyl5-(1-phenylcyclopropyl)thiazole-2-carboxylate (100 mg, 0.36 mmol) intetrahydrofuran (2 mL) and water (1 mL). The reaction mixture wasstirred at room temperature overnight, concentrated under reducedpressure and diluted with water (10 mL). The resulting mixture wasadjusted to pH=5 with aqueous hydrochloric acid (1 N, 10 mL) andextracted with ethyl acetate (3×10 mL). The combined organic layers werewashed with brine, dried over anhydrous sodium sulfate, filtered andconcentrated under vacuum to afford the title compound (49 mg, 56%) as ayellow oil, which was used directly in the next step without furtherpurification. LC-MS (Method C): m/z=246.1 [M+H]⁺, 1.200 min.

Step 7.S)—N-(5-methyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepin-3-yl)-5-(1-phenylcyclopropyl)thiazole-2-carboxamide

The crude product obtained using Amide Coupling Procedure C was purifiedby Prep-HPLC with the following conditions: column: Xbridge Prep C18,19×250 mm, 5 μm; Mobile phase: Phase A: water (10 mmol/L NH₄HCO₃); PhaseB: ACN (45% to 65% over 7 min); Detector, UV220 & 254 nm to afford thetitle compound. ¹H NMR (400 MHz, DMSO-d₆) δ 8.95 (d, J=7.5 Hz, 1H), 8.36(dd, J=4.7, 1.6 Hz, 1H), 7.74 (s, 1H), 7.70 (dd, J=7.9, 1.6 Hz, 1H),7.40-7.23 (m, 6H), 4.88-4.71 (m, 2H), 4.52 (dd, J=9.1, 6.7 Hz, 1H), 3.35(s, 3H), 1.47 (s, 4H). LC-MS (Method T): m/z=421.3 [M+H]⁺, 1.729 min.

Example 64:(S)-1-benzyl-4-fluoro-N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-pyrazole-3-carboxamide

Step 1: Preparation of 1-benzyl-4-fluoro-1H-pyrazole-3-carboxylic acid

Sodium hydride (60%, 1 g, 25 mmol) was added to a solution of ethyl4-fluoro-1H-pyrazole-3-carboxylate (1.2 g, 7.6 mmol) inN,N-dimethylformamide (20 mL) at 0° C. The resulting mixture was stirredfor 0.5 hour at room temperature followed by adding benzyl bromide (1.36g, 8.0 mmol). The resulting mixture was stirred for 2 hours at roomtemperature. Water (20 mL) was added dropwise. The resulting solutionwas then stirred at room temperature for 5 hours. The pH value of thesolution was adjusted to 7 with aqueous hydrochloric acid (1 N, 20 mL).The resulting solution was extracted with ethyl acetate (3×50 mL). Thecombined organic layers were washed with brine, dried over anhydroussodium sulfate, filtered and concentrated under vacuum. The residue wasthen purified by Prep-HPLC with the following conditions: Column:XBridge C18 OBD Prep Column, 5 μm, 19 mm×250 mm; Mobile Phase A: water(0.1% formic acid), Mobile Phase B: ACN; Flow rate: 20 mL/min; Gradient:30% B to 60% B over 7 min; 254 nm to afford the title compound (370 mg,22%) as a white solid. LC-MS (Method D): m/z=221.1 [M+H]⁺, 1.206 min.

Step 2: Preparation of(S)-1-benzyl-4-fluoro-N-(5-methyl-4-oxo-2,3,4,5tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-pyrazole-3-carboxamide

The crude product obtained using Amide Coupling Procedure C was purifiedby Prep-HPLC with the following conditions: Column: XBridge Prep C18 OBDColumn 19×150 mm, 5 μm; Mobile Phase A: water (0.05% NH₃H₂O), MobilePhase B: ACN; Flow rate: 20 mL/min; Gradient: 25% B to 55% B over 7 min;Detector, UV220 & 254 nm to afford the title compound. ¹H NMR (400 MHz,Chloroform-d) δ 7.66 (d, J=6.8 Hz, 1H), 7.43-7.40 (m, 3H), 7.39-7.21 (m,6H), 5.26 (s, 2H), 5.13-5.07 (m, 1H), 4.83-4.81 (m, 1H), 4.31-4.26 (m,1H), 3.47 (s, 3H). LC-MS (Method J): m/z=395.2 [M+H]⁺, 1.474 min.

Example 65:N-[(4S,9aR)-5-oxo-octahydropyrrolo[2,1-c][1,4]oxazepin-4-yl]-5-benzyl-4H-1,2,4-triazole-3-carboxamide

The title compound was prepared from N-Boc-D-prolinol using theprocedure described in Example 27.

The crude product was purified by column chromatography on KP-NHmodified silica gel (CH₂Cl₂-MeOH, 97:3 to 90:10) to afford the titlecompound. ¹H NMR (400 MHz, CDCl₃) δ 8.31 (d, J=6.3 Hz, 1H), 7.37-7.23(m, 5H), 4.90 (ddd, J=9.3, 6.3, 2.8 Hz, 1H), 4.21 (s, 2H), 4.17 (dd,J=11.7, 2.6 Hz, 1H), 4.09 (q, J=8.8 Hz, 1H), 3.98 (d, J=12.5 Hz, 1H),3.93-3.82 (m, 1H), 3.52-3.39 (m, 2H), 3.24 (dd, J=12.8, 9.3 Hz, 1H),2.33-2.17 (m, 1H), 2.01-1.90 (m, 1H), 1.87-1.70 (m, 1H), 1.66-1.51 (m,1H). LC-MS (Method A): m/z=356.4 [M+H]⁺, 0.71 min.

Example 66:(S)—N-(5-methyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepin-3-yl)-5-(1-phenylcyclopropyl)-1,3,4-oxadiazole-2-carboxamide

Step 1: Preparation of 1-phenylcyclopropanecarbohydrazide

Triethylamine (93.5 g, 925.5 mmol) was added to a stirring mixture ofhydrazine dihydrochloride (32.1 g, 308.6 mmol) in N,N-dimethylformamide(300 mL). The resulting mixture was added to a mixture of1-phenylcyclopropanecarboxylic acid (10.0 g, 61.7 mmol),0-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (28.2 g, 74.0 mmol) and N,N-diisopropylethylamine(23.9 g, 185.1 mmol) in N,N-dimethylformamide (100 mL). The reactionmixture was stirred at room temperature for 2 hours, diluted with water(500 mL) and extracted with ethyl acetate (5×100 mL). The combinedorganic layers were washed with brine, dried over anhydrous sodiumsulfate, filtered and concentrated under vacuum. The residue waspurified by column chromatography (ethyl acetate/petroleum ether, 1/3)to afford the title compound (6 g, 55.2%) as a white solid. LC-MS(Method E): m/z=177.0 [M+H]⁺, 1.139 min.

Step 2: Preparation of ethyl2-oxo-2-(2-(1-phenylcyclopropanecarbonyl)hydrazinyl)acetate

Ethyl 2-chloro-2-oxoacetate (1.56 g, 11.4 mmol) was added to a stirringsolution of 1-phenylcyclopropane carbohydrazide (2.00 g, 11.4 mmol) andtriethylamine (3.44 g, 34.1 mmol) in dichloromethane (40 mL) at roomtemperature. The reaction mixture was stirred for 12 hours at roomtemperature, quenched by the addition of water (40 mL) and extractedwith dichloromethane (3×50 mL). The combined organic layers were washedwith brine, dried over anhydrous sodium sulfate, filtered andconcentrated under vacuum. The residue was purified by columnchromatography (ethyl acetate/petroleum ether, 1/3) to afford the titlecompound (3 g, 96.7%) as a yellow oil. LC-MS (Method E): m/z=277.0[M+H]⁺, 0.676 min.

Step 3: Preparation of ethyl5-(1-phenylcyclopropyl)-1,3,4-oxadiazole-2-carboxylate

Tosyl chloride (0.80 g, 3.62 mmol) was added to a stirring solution ofethyl 2-oxo-2-(2-(1-phenylcyclopropanecarbonyl)hydrazinyl)acetate (1.0g, 3.62 mmol) and triethylamine (1.1 g, 6.6 mmol) in dichloromethane (25mL). The reaction mixture was stirred for 12 hours at room temperature,quenched by the addition of water (20 mL) and extracted withdichloromethane (3×25 mL). The combined organic layers were washed withbrine, dried over anhydrous sodium sulfate, filtered and concentratedunder vacuum. The residue was purified by column chromatography (ethylacetate/petroleum ether, 1/3) to afford the title compound (0.80 g,85.6%) as a yellow oil. LC-MS (Method C): m/z=259.0 [M+H]⁺, 1.457 min.

Step 4: Preparation of(S)—N-(5-methyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepin-3-yl)-5-(1-phenylcyclopropyl)-1,3,4-oxadiazole-2-carboxamide

The crude product obtained using the procedure described in Example 54was purified by Prep-HPLC with the following conditions: Column: XBridgePrep C18 OBD Column, 5 μm, 19×150 mm; mobile phase, water (10 mmol/LNH₄HCO₃), ACN (40% ACN to 70% B over 7 min); detector, UV 254 & 220 nmto afford the title compound. ¹H NMR (400 MHz, DMSO-d₆) δ 9.49 (s, 1H),8.37-8.35 (m, 1H), 7.71-7.69 (m, 1H), 7.42-7.30 (m, 6H), 4.82-4.80 (m,1H), 4.75-4.73 (m, 1H), 4.54-4.50 (m, 1H), 3.33 (s, 3H), 1.70-1.69 (m,2H), 1.54-1.50 (m, 2H). LC-MS (Method T): m/z=406.3 [M+H]⁺, 2.463 min.

Example 67A and 67B:5-benzyl-N-((1aR,2S,8bS)-4-methyl-3-oxo-1,1a,2,3,4,8b-hexahydrobenzo[b]cyclopropa[d]azepin-2-yl)-4H-1,2,4-triazole-3-carboxamide(67A) and5-benzyl-N-((1aS,2R,8bR)-4-methyl-3-oxo-1,1a,2,3,4,8b-hexahydrobenzo[b]cyclopropa[d]azepin-2-yl)-4H-1,2,4-triazole-3-carboxamide(67B)

Step 1: Preparation of tert-butyl(trans-4-methyl-3-oxo-1,1a,2,3,4,8b-hexahydrobenzo[b]cyclopropa[d]azepin-2-yl)carbamate

A solution of tert-butyl(cis-4-methyl-3-oxo-1,1a,2,3,4,8b-hexahydrobenzo[b]cyclopropa[d]azepin-2-yl)carbamate(100 mg, 0.33 mmol) in 1,8-diazabicyclo[5.4.0]undec-7-ene was stirred at90° C. overnight. The solution was purified by TLC (ethylacetate/petroleum ether, 1/8) to afford the title compound (60 mg, 60%)as a yellow solid. LC-MS (Method E): m/z=325.0 [M+Na]⁺, 0.930 min.

Step 2: Preparation oftrans-2-amino-4-methyl-1,1a,2,8b-tetrahydrobenzo[b]cyclopropa[d]azepin-3(4H)-one hydrochloride

To a solution of tert-butyl(trans-4-methyl-3-oxo-1,1a,2,3,4,8b-hexahydrobenzo[b]cyclopropa[d]azepin-2-yl)carbamate(60 mg, 0.20 mmol) in 1,4-dioxane (2 mL) was added a solution ofhydrogen chloride in 1,4-dioxane (4 M, 5 mL, 20 mmol). The reactionmixture was stirred for 2 hours at room temperature and concentratedunder high vacuum to afford the title compound (40 mg crude) as a yellowsolid, which was used directly in the next step without furtherpurification. LC-MS (Method S): m/z=203.3 [M+H]⁺, 0.592 min.

Step 3: Preparation oftrans-5-benzyl-N-(4-methyl-3-oxo-1,1a,2,3,4,8b-hexahydrobenzo[b]cyclopropa[d]azepin-2-yl)-4H-1,2,4-triazole-3-carboxamide

The crude product obtained using Amide Coupling Procedure C was purifiedby Prep-HPLC with the following conditions: Column: XBridge Prep C18 OBDColumn, 5 μm, 19×150 mm; Mobile Phase A: water (0.05% TFA), Mobile PhaseB: ACN; Flow rate: 20 mL/min; Gradient: 35% B to 65% B over 7 min;254/220 nm to afford the title compound. LC-MS (Method J): m/z=388.2[M+H]⁺, 1.305 min.

Step 7. Preparation of5-benzyl-N-((1aR,2S,8bS)-4-methyl-3-oxo-1,1a,2,3,4,8b-hexahydrobenzo[b]cyclopropa[d]azepin-2-yl)-4H-1,2,4-triazole-3-carboxamide(First Eluting Isomer) and5-benzyl-N-((1aS,2R,8bR)-4-methyl-3-oxo-1,1a,2,3,4,8b-hexahydrobenzo[b]cyclopropa[d]azepin-2-yl)-4H-1,2,4-triazole-3-carboxamide (SecondEluting Isomer)

The enantiomers oftrans-5-benzyl-N-(4-methyl-3-oxo-1,1a,2,3,4,8b-hexahydrobenzo[b]cyclopropa[d]azepin-2-yl)-4H-1,2,4-triazole-3-carboxamide(25 mg, 0.065 mmol) were separated by Prep-Chiral-HPLC with thefollowing conditions: Column: Chiralpak ID-2, 2×25 cm, 5 μm; MobilePhase A: hexane, Mobile Phase B: EtOH; Flow rate: 17 mL/min; Gradient:50% B to 50% B over 22 min; UV 254 & 220 nm; RT 1: 11.72 min; RT 2:18.02 min to afford the title compounds.

Example 67A (first eluting isomer): ¹H NMR (300 MHz, Methanol-d₄) δ 7.56(d, J=7.5 Hz, 1H), 7.42-7.19 (m, 9H), 4.23-4.13 (m, 3H), 3.43 (s, 3H),2.25-2.15 (m, 1H), 1.72-1.58 (m, 1H), 1.25-1.13 (m, 1H), 0.79-0.65 (m,1H). LC-MS (Method D): m/z=388.2 [M+H]⁺, 1.806 min.

Example 67B (second eluting isomer): ¹H NMR (300 MHz, Methanol-d₄) δ7.56 (d, J=7.5 Hz, 1H), 7.42-7.19 (m, 9H), 4.23-4.13 (m, 3H), 3.43 (s,3H), 2.25-2.15 (m, 1H), 1.72-1.58 (m, 1H), 1.25-1.13 (m, 1H), 0.79-0.65(m, 1H). LC-MS (Method D): m/z=388.2 [M+H]⁺, 1.812 min.

Example 68A:(R)-5-benzyl-N-(4,5-dihydrobenzo[b]imidazo[1,2-d][1,4]oxazepin-4-yl)-4H-1,2,4-triazole-3-carboxamide

The crude product obtained using Amide Coupling Procedure C was purifiedby Prep-HPLC with the following conditions: Column: X Bridge Prep C18OBD Column 19×150 mm 5 μm; Mobile Phase A: water (10 mmol/L NH₄HCO₃),Mobile Phase B: ACN; Flow rate: 30 mL/min; Gradient: 25% B to 55% B over7 min; UV 254 & 220 nm to afford the title compound. ¹H NMR (300 MHz,DMSO-d₆) δ 14.42 (s, 1H), 8.80 (br. s, 1H), 7.70-7.64 (m, 2H), 7.43-7.25(m, 8H), 7.07 (d, J=1.2 Hz, 1H), 5.40-5.29 (m, 1H), 4.64-4.49 (m, 2H),4.14 (s, 2H). LC-MS (Method D): m/z=387.1 [M+H]⁺, 1.322 min.

Example 68B:(S)-5-benzyl-N-(4,5-dihydrobenzo[b]imidazo[1,2-d][1,4]oxazepin-4-yl)-4H-1,2,4-triazole-3-carboxamide

The crude product obtained using Amide Coupling Procedure C was purifiedby Prep-HPLC with the following conditions: Column: X Bridge Prep C18OBD Column 19×150 mm 5 μm; Mobile Phase A: water (10 mmol/L NH₄HCO₃),Mobile Phase B: ACN; Flow rate: 30 mL/min; Gradient: 25% B to 55% B over7 min; UV 254 & 220 nm to afford the title compound ¹H NMR (300 MHz,DMSO-d₆) δ 14.39 (s, 1H), 8.80 (s, 1H), 7.70-7.65 (m, 2H), 7.41-7.22 (m,8H), 7.07 (d, J=1.2 Hz, 1H), 5.40-5.31 (m, 1H), 4.64-4.49 (m, 2H), 4.14(s, 2H). LC-MS (Method D): m/z=387.1 [M+H]⁺, 1.325 min.

Example 69A and 69B:(S)-5-benzyl-N-(5,6-dihydro-4H-benzo[f][1,2,4]triazolo[4,3-a]azepin-4-yl)-4H-1,2,4-triazole-3-carboxamide(69A) and(R)-5-benzyl-N-(5,6-dihydro-4H-benzo[f][1,2,4]triazolo[4,3-a]azepin-4-yl)-4H-1,2,4-triazole-3-carboxamide(69B)

Step 1: Preparation of benzyl(5,6-dihydro-4H-benzo[f][1,2,4]triazolo[4,3-a]azepin-4-yl)carbamate

Formylhydrazine (0.54 g, 9 mmol) was added to a stirring solution of(S)-benzyl (2-thioxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-3-ylcarbamate(1.00 g, 3 mmol) in 1-butanol (15 mL). After stirring at 60° C. for 1hour and at 150° C. for 15 hours, the reaction mixture was concentratedunder high vacuum, diluted with water (50 mL) and extracted with ethylacetate (3×100 mL). The combined organic layers were washed with brine,dried over anhydrous sodium sulfate, filtered and concentrated undervacuum. The residue was purified by column chromatography (ethylacetate/petroleum ether, 1/3) to afford the title compound (0.64 g, 63%)as a white solid. LC-MS (Method E): m/z=335.1 [M+H]⁺, 0.746 min.

Step 2: Preparation of5,6-dihydro-4H-benzo[f][1,2,4]triazolo[4,3-a]azepin-4-amine

Benzyl(5,6-dihydro-4H-benzo[f][1,2,4]triazolo[4,3-a]azepin-4-yl)carbamate(0.63 g, 1.9 mmol) in methanol (20 mL) was hydrogenated in the presenceof palladium on carbon (10%, 0.2 g) under a hydrogen atmosphere (2-3atm). The reaction mixture was stirred at room temperature for 6 hoursunder a hydrogen atmosphere. The solids were removed by filtration andthe filtrate was concentrated under high vacuum to afford the titlecompound (0.36 g, 95%) as a colorless oil. LC-MS (Method C): m/z=201.1[M+H]⁺, 0.848 min.

Step 3: Preparation of(S)-5,6-dihydro-4H-benzo[f][1,2,4]triazolo[4,3-a]azepin-4-amine and(R)-5,6-dihydro-4H-benzo[f][1,2,4]triazolo[4,3-a]azepin-4-amine

The enantiomers of5,6-dihydro-4H-benzo[f][1,2,4]triazolo[4,3-a]azepin-4-amine (0.36 g, 1.8mmol) were separated by Prep-Chiral-HPLC with the following conditions:Column: Chiralpak IC, 2×25 cm, 5 μm; Mobile Phase A: MTBE, Mobile PhaseB: EtOH; Flow rate: 15 mL/min; Gradient: 60% B to 60% B over 23 min;220/254 nm; RT 1: 12.04 min; RT 2: 20.81 min to afford the titlecompounds.

(S)-5,6-dihydro-4H-benzo[f][1,2,4]triazolo[4,3-a]azepin-4-amine (firsteluting isomer): 110 mg (62%) as a white solid. LC-MS (Method C):m/z=201.1 [M+H]⁺, 0.848 min.

(R)-5,6-dihydro-4H-benzo[f][1,2,4]triazolo[4,3-a]azepin-4-amine (secondeluting isomer): 110 mg (62%) as a white solid. LC-MS (Method C):m/z=201.1 [M+H]⁺, 0.848 min.

Step 4: Preparation of(S)-5-benzyl-N-(5,6-dihydro-4H-benzo[f][1,2,4]triazolo[4,3-a]azepin-4-yl)-4H-1,2,4-triazole-3-carboxamide

The crude product obtained using Amide Coupling Procedure C was purifiedby Prep-HPLC with the following conditions: Column: XBridge C18 OBD PrepColumn, 100 Å, 5 μm, 19 mm×250 mm; Mobile Phase A: water (10 mmol/LNH₄HCO₃), Mobile Phase B: ACN; Flow rate: 20 mL/min; Gradient: 20% B to40% B over 7 min; UV 254 & 220 nm to afford the title compound. ¹H NMR(300 MHz, DMSO-d₆) δ 14.39 (s, 1H), 8.93 (m, 2H), 7.62-7.59 (m, 1H),7.56-7.43 (m, 3H), 7.38-7.23 (m, 5H), 5.02-4.92 (m, 1H), 4.14 (s, 2H),2.84-2.77 (m, 1H), 2.60-2.55 (m, 1H), 2.48-2.40 (m, 2H). LC-MS (MethodD): m/z=386.2 [M+H]⁺, 1.489 min.

Example 69B:(R)-5-benzyl-N-(5,6-dihydro-4H-benzo[f][1,2,4]triazolo[4,3-a]azepin-4-yl)-4H-1,2,4-triazole-3-carboxamide

The crude product obtained using Amide Coupling Procedure C was purifiedby Prep-HPLC with the following conditions: Column: X Bridge C18 OBDPrep Column, 100 Å, 5 μm, 19 mm×250 mm; Mobile Phase A: water (10 mmol/LNH₄HCO₃), Mobile Phase B: ACN; Flow rate: 20 mL/min; Gradient: 20% B to40% B over 7 min; UV 254 & 220 nm to afford the title compound ¹H NMR(300 MHz, DMSO-d₆) δ 14.39 (s, 1H), 8.93 (m, 2H), 7.62-7.59 (m, 1H),7.56-7.43 (m, 3H), 7.37-7.22 (m, 5H), 5.02-4.92 (m, 1H), 4.14 (s, 2H),2.84-2.73 (m, 1H), 2.58-2.54 (m, 1H), 2.48-2.41 (m, 2H). LC-MS (MethodD): m/z=386.2 [M+H]⁺, 1.486 min.

Example 70A:(R)-5-benzyl-N-(4,5-dihydrobenzo[b]imidazo[1,2-d][1,4]oxazepin-4-yl)isoxazole-3-carboxamide

Step 1: Preparation of (S)-benzyl(4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)carbamate

A solution of potassium carbonate (4.8 g, 35 mmol) in water (9 mL) wasadded to a solution of(S)-3-amino-2,3-dihydrobenzo[b][1,4]oxazepin-4(5H)-one hydrochloride(1.5 g, 7 mmol) in dichloromethane (70 mL) and then benzyl chloroformate(1.8 g, 10.5 mmol) was added. The reaction mixture was stirred at roomtemperature for 16 hours. The precipitate was collected by filtration,washed with water (20 mL) and dried under high vacuum to afford thetitle compound (1.44 g, 66%) as a white solid. LC-MS (Method C):m/z=313.1 [M+H]⁺, 1.365 min.

Step 2: Preparation of (S)-benzyl4-thioxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-ylcarbamate

Lawesson's reagent (2.43 g, 6 mmol) was added to a solution of(S)-benzyl 4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-ylcarbamate(1.9 g, 6 mmol) in tetrahydrofuran (50 mL) and the reaction mixture wasstirred under a nitrogen atmosphere for 16 hours at room temperature.The precipitate was removed by filtration and the filtrate wasconcentrated under reduced pressure. The resulting residue was dilutedwith water (50 mL) and extracted with ethyl acetate (3×100 mL). Thecombined organic layers were washed with brine, dried over sodiumsulfate and concentrated under reduced pressure to give the titlecompound (1.85 g crude) as a light yellow solid. LC-MS (Method E):m/z=351.0 [M+Na]⁺, 0.946 min.

Step 3: Preparation of (R)-benzyl4-(2,2-dimethoxyethylamino)-2,3-dihydrobenzo[b][1,4]-oxazepin-3-ylcarbamate

2,2-Dimethoxyethanamine (2.37 g, 22.6 mmol) was added to a solution of(S)-benzyl4-thioxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-ylcarbamate (1.85 g,5.65 mmol) and mercury dichloride (2.0 g, 7.35 mmol) in tetrahydrofuran(50 mL). The reaction mixture was stirred at 55° C. for 2 hours andcooled to room temperature. Solids were removed by filtration and thefiltrate was concentrated under reduced pressure. The residue wasdiluted with water (100 mL) and extracted with dichloromethane (3×100mL). The combined organic layers were washed with brine, dried overanhydrous sodium sulfate and concentrated under reduced pressure to givethe title compound (2.20 g, 98%) as a light yellow oil. LC-MS (MethodC): m/z=400.2 [M+H]⁺, 1.157 min.

Step 4: Preparation of benzyl(4,5-dihydrobenzo[b]imidazo[1,2-d][1,4]oxazepin-4-yl)carbamate

A solution of (R)-benzyl4-(2,2-dimethoxyethylamino)-2,3-dihydrobenzo[b][1,4]-oxazepin-3-ylcarbamate(2.2 g, 5.5 mmol) in formic acid (15 mL, 96%) was stirred at 100° C. for2 hours. The black sediment was removed by filtration and the filtratewas concentrated under reduced pressure. The resulting residue wasdiluted with water (50 mL), basified with aqueous sodium hydroxide (1 N,30 mL) to pH=6 and extracted with ethyl acetate (3×100 mL). The combinedorganic layers were washed with brine, dried over anhydrous sodiumsulfate, filtered and concentrated under reduced pressure. The residuewas purified by column chromatography (ethyl acetate/petroleum ether,1/3) to afford the title compound (0.45 g, 24%) as a white solid. LC-MS(Method E): m/z=336.0 [M+H]⁺, 0.655 min.

Step 5: Preparation of (S)-benzyl(4,5-dihydrobenzo[b]imidazo[1,2-d][1,4]oxazepin-4-yl)carbamate (FirstEluting Isomer) and (R)-benzyl(4,5-dihydrobenzo[b]imidazo[1,2-d][1,4]oxazepin-4-yl)carbamate (SecondEluting Isomer)

The enantiomers of benzyl(4,5-dihydrobenzo[b]imidazo[1,2-d][1,4]oxazepin-4-yl)carbamate (450 mg,1.35 mmol) were separated by SFC with the following conditions: Column:CHIRALPAK-IC-SFC, 5 cm×25 cm (5 μm); Mobile Phase A: CO₂ 50%, MobilePhase B: MeOH: 50%; Flow rate: 150 mL/min; 220 nm; RT 1: 5.65 min; RT 2:6.91 min to afford the title compounds:

(S)-benzyl(4,5-dihydrobenzo[b]imidazo[1,2-d][1,4]oxazepin-4-yl)carbamate: (250 mg,56%) as a white solid. LC-MS (Method E): m/z=336.0 [M+H]⁺, 0.655 min.

(R)-benzyl(4,5-dihydrobenzo[b]imidazo[1,2-d][1,4]oxazepin-4-yl)carbamate (secondeluting isomer): (200 mg, 45%) as a white solid. LC-MS (Method E):m/z=336.0 [M+H]⁺, 0.655 min.

Step 6: Preparation of(R)-4,5-dihydrobenzo[b]imidazo[1,2-d][1,4]oxazepin-4-amine

(R)-Benzyl(4,5-dihydrobenzo[b]imidazo[1,2-d][1,4]oxazepin-4-yl)carbamate (0.25 g,0.75 mmol) in methanol (20 mL) was hydrogenated in the presence ofpalladium on carbon (10%, 0.5 g) under a hydrogen atmosphere (2-3 atm).The reaction mixture was stirred for 6 hours at room temperature under ahydrogen atmosphere. The solids were removed by filtration and thefiltrate was concentrated under high vacuum to afford the title compound(0.14 g, 93%) as a white solid. LC-MS (Method C): m/z=202.1 [M+H]⁺,0.758 min.

Step 7. Preparation of(R)-5-benzyl-N-(4,5-dihydrobenzo[b]imidazo[1,2-d][1,4]oxazepin-4-yl)isoxazole-3-carboxamide

The crude product obtained using Amide Coupling Procedure C was purifiedby Prep-HPLC with the following conditions: Column: X Bridge Prep C18OBD Column, 5 μm, 19×150 mm; Mobile Phase A: water (10 mmol/L NH₄HCO₃),Mobile Phase B: ACN; Flow rate: 20 mL/min; Gradient: 20% B to 65% B over7 min; UV 254 & 220 nm to afford the title compound. ¹H NMR (300 MHz,DMSO-d₆) δ 9.24 (d, J=8.7 Hz, 1H), 7.71-7.65 (m, 2H), 7.40-7.28 (m, 8H),7.07 (d, J=1.2 Hz, 1H), 6.59 (s, 1H), 5.43-5.34 (m, 1H), 4.61-4.46 (m,2H), 4.24 (s, 2H). LC-MS (Method D): m/z=387.1 [M+H]⁺, 1.579 min.

Example 70B:(S)-5-benzyl-N-(4,5-dihydrobenzo[b]imidazo[1,2-d][1,4]oxazepin-4-yl)isoxazole-3-carboxamide

Step 1: Preparation of(S)-4,5-dihydrobenzo[b]imidazo[1,2-d][1,4]oxazepin-4-amine

(S)-Benzyl(4,5-dihydrobenzo[b]imidazo[1,2-d][1,4]oxazepin-4-yl)carbamate (0.2 g,0.6 mmol) in methanol (20 mL) was hydrogenated in the presence ofpalladium on carbon (10%, 0.2 g) under a hydrogen atmosphere (2-3 atm).The reaction mixture was stirred at room temperature for 6 hours under ahydrogen atmosphere. The solids were removed by filtration and thefiltrate was concentrated under high vacuum to afford the title compound(0.11 g, 92%) as a white solid. LC-MS (Method C): m/z=202.1 [M+H]⁺,0.758 min.

Step 2: Preparation of(S)-5-benzyl-N-(4,5-dihydrobenzo[b]imidazo[1,2-d][1,4]oxazepin-4-yl)isoxazole-3-carboxamide

The crude product obtained using Amide Coupling Procedure C was purifiedby Prep-HPLC with the following conditions: Column: X Bridge Prep C18OBD Column, 5 μm, 19×150 mm; Mobile Phase A: water (10 mmol/L NH₄HCO₃),Mobile Phase B: ACN; Flow rate: 20 mL/min; Gradient: 45% B to 57% B over7 min; UV 254 & 220 nm to afford the title compound. ¹H NMR (300 MHz,DMSO-d₆) δ 9.24 (d, J=8.4 Hz, 1H), 7.71-7.65 (m, 2H), 7.42-7.28 (m, 8H),7.07 (d, J=1.5 Hz, 1H), 6.59 (s, 1H), 5.43-5.34 (m, 1H), 4.62-4.45 (m,2H), 4.24 (s, 2H). LC-MS (Method V): m/z=387.1 [M+H]⁺, 2.491 min.

Example 71A:(S)-5-benzyl-N-(5,6-dihydro-4H-benzo[f][1,2,4]triazolo[4,3-a]azepin-4-yl)isoxazole-3-carboxamide

The crude product obtained using Amide Coupling Procedure C was purifiedby Prep-HPLC with the following conditions: Column: X Bridge Prep C18OBD Column, 5 μm, 19×150 mm; Mobile Phase A: water (10 mmol/L NH₄HCO₃),Mobile Phase B: ACN; Flow rate: 20 mL/min; Gradient: 30% B to 58% B over7 min; UV 254 & 220 nm to afford the title compound. ¹H NMR (300 MHz,DMSO-d₆) δ 9.36 (d, J=8.4 Hz, 1H), 8.93 (s, 1H), 7.62-7.59 (m, 1H),7.55-7.43 (m, 3H), 7.40-7.26 (m, 5H), 6.58 (s, 1H), 5.01-4.92 (m, 1H),4.24 (s, 2H), 2.86-2.77 (m, 1H), 2.49-2.39 (m, 3H). LC-MS (Method D):m/z=386.2 [M+H]⁺, 1.805 min.

Example 71B:(R)-5-benzyl-N-(5,6-dihydro-4H-benzo[f][1,2,4]triazolo[4,3-a]azepin-4-yl)isoxazole-3-carboxamide

The crude product obtained using Amide Coupling Procedure C was purifiedby Prep-HPLC with the following conditions: Column: X Bridge Prep C18OBD Column, 5 μm, 19×150 mm; Mobile Phase A: water (10 mmol/L NH₄HCO₃),Mobile Phase B: ACN; Flow rate: 20 mL/min; Gradient: 30% B to 60% B over7 min; UV 254 & 220 nm to afford the title compound. ¹H NMR (300 MHz,DMSO-d₆) δ 9.36 (d, J=8.1 Hz, 1H), 8.93 (s, 1H), 7.63-7.59 (m, 1H),7.55-7.43 (m, 3H), 7.40-7.26 (m, 5H), 6.58 (s, 1H), 5.01-4.92 (m, 1H),4.24 (s, 2H), 2.86-2.77 (m, 1H), 2.49-2.38 (m, 3H). LC-MS (Method D):m/z=386.2 [M+H]⁺, 1.809 min.

Example 72:(S)—N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-5-(1-phenylcyclopropyl)-1H-pyrazole-3-carboxamide

Step 1: Preparation ofN-methoxy-N-methyl-1-phenylcyclopropanecarboxamide

N,N-diisopropylethylamine (47.2 g, 219.6 mmol) was added to a mixture of1-phenylcyclopropanecarboxylic acid (10.0 g, 61.7 mmol),O,N-dimethylhydroxylamine hydrochloride (6.5 g, 67.8 mmol),N-(3-dimethylaminopropyl))-N′-ethylcarbodiimide hydrochloride (14.2 g,73.9 mmol) and 1-hydroxybenzotriazole (10.0 g, 73.9 mmol) inN,N-dimethylformamide (60 mL). The resulting mixture was stirredovernight at room temperature, diluted with water (300 mL) and extractedethyl acetate (3×200 mL). The combined organic phases were washed withbrine, dried over sodium sulfate, filtered and concentrated underreduced pressure. The residue was purified by column chromatography(ethyl acetate/petroleum ether, 1/20) to afford the title compound (11.2g, 89.6%) as colorless oil. LC-MS (Method K): m/z=206.0 [M+H]⁺, 1.489min.

Step 2: Preparation of 1-(1-phenylcyclopropyl)ethanone

To a solution of methylmagnesium bromide (3 M, 14 mL, 42 mmol) intetrahydrofuran was added a solution ofN-methoxy-N-methyl-1-phenylcyclopropanecarboxamide (11.2 g, 24.4 mmol)in tetrahydrofuran (50 mL) at 0° C. The resulting mixture was stirredovernight at room temperature, quenched with saturated ammonium chloride(50 mL), extracted with ethyl acetate (3×80 mL). The combined organiclayers were washed with brine, dried with sodium sulfate andconcentrated under reduced pressure. The residue was purified by columnchromatography (ethyl acetate/petroleum ether, 1/20) to afford the titlecompound (7.4 g, 85%) as a colorless oil. LC-MS (Method E): m/z=161.0[M+H]⁺, 0.889 min.

Step 3: Preparation of ethyl 2,4-dioxo-4-(1-phenylcyclopropyl)butanoate

To a mixture of 1-(1-phenylcyclopropyl)ethanone (1.92 g, 12 mmol) anddiethyl oxalate (2.1 g, 14.4 mmol) in toluene (8 mL) was added potassium2-methylpropan-2-olate (1.7 g, 15.6 mmol) at 0° C. The resulting mixturewas stirred at room temperature for 4 hours and concentrated undervacuum. The residue was diluted with water (20 mL). The resultingmixture was neutralized to pH=6 with aqueous hydrochloric acid (1 N) andextracted with ethyl acetate (3×20 mL). The combined organic layers werewashed with brine, dried over anhydrous sodium sulfate, filtered andconcentrated under reduced pressure. The residue was purified by columnchromatography (ethyl acetate/petroleum ether, 1/10) to afford the titlecompound (1.95 g, 61%) as a yellow solid. LC-MS (Method S): m/z=261.2[M+H]⁺, 1.076 min.

Step 4: Preparation of ethyl5-(1-phenylcyclopropyl)-1H-pyrazole-3-carboxylate

To a solution of ethyl 2,4-dioxo-4-(1-phenylcyclopropyl)butanoate (800mg, 3.0 mmol) in ethanol (8 mL) was added hydrazine hydrate (80% aqueoussolution, 200 mg, 3.0 mmol). The reaction mixture was stirred at 80° C.for 1.5 hours and concentrated under vacuum. The resulting residue waspurified by column chromatography (ethyl acetate/petroleum ether, 1/3)to afford the title compound (550 mg, 70%) as a yellow solid. LC-MS(Method K): m/z=256.7 [M+H]⁺, 1.640 min.

Step 5: Preparation of 5-(1-phenylcyclopropyl)-1H-pyrazole-3-carboxylicacid

To a solution of ethyl 5-(1-phenylcyclopropyl)-1H-pyrazole-3-carboxylate(470 mg, 1.8 mmol) in methanol (4.5 mL) and water (1.5 mL) was addedsodium hydroxide (432 mg, 10.8 mmol). The reaction mixture was stirredovernight at room temperature and concentrated under vacuum. The residuewas diluted with water (20 mL) and adjusted to pH=5 using aqueoushydrochloric acid (1 N) and extracted with ethyl acetate (3×10 mL). Thecombined organic layers were washed with brine, dried over anhydroussodium sulfate and concentrated under vacuum to afford the titlecompound (280 mg crude) as a yellow solid, which was used directly inthe next step without further purification. LC-MS (Method K): m/z=228.7[M+H]⁺, 1.434 min.

Step 6: Preparation of(S)—N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-5-(1-phenylcyclopropyl)-1H-pyrazole-3-carboxamide

The crude product obtained using Amide Coupling Procedure C was purifiedby Prep-HPLC with the following conditions: Column: XBridge Prep C18 OBDColumn, 5 μm, 19×150 mm; mobile phase, water (10 mmol/L NH₄HCO₃), ACN(40% ACN to 65% B over 7 min); detector, UV 254 & 220 nm to afford thetitle compound. ¹H NMR (300 MHz, DMSO-d₆) 13.16 (s, 1H), 8.06 (d, J=8.1Hz, 1H), 7.55-7.46 (m, 1H), 7.38-7.17 (m, 8H), 6.34 (s, 1H), 4.93-4.75(m, 1H), 4.60-4.28 (m, 2H), 3.31 (s, 3H), 1.39-1.16 (m, 4H). LC-MS(Method O): m/z=403.05 [M+H]⁺, 1.511 min.

Example 73:(S)—N-(5-methyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepin-3-yl)-5-(1-phenylcyclopropyl)-1H-pyrazole-3-carboxamide

The crude product obtained using Amide Coupling Procedure C was purifiedby Prep-HPLC with the following conditions: Column: X Bridge C18 OBDPrep Column, 100 Å, 5 μm, 19 mm×250 mm; Mobile Phase A: water (10 mmol/LNH₄HCO₃), Mobile Phase B: ACN; Flow rate: 20 mL/min; Gradient: 30% B to50% B over 7 min; UV 254 & 220 nm to afford the title compound. ¹H NMR(300 MHz, DMSO-d₆) δ 13.18 (s, 1H), 8.38-8.35 (m, 1H), 8.24 (d, J=7.5Hz, 1H), 7.73-7.69 (m, 1H), 7.36-7.20 (m, 6H), 6.54-6.35 (m, 1H),4.90-4.80 (m, 1H), 4.70-4.62 (m, 1H), 4.53-4.46 (m, 1H), 3.35 (s, 3H),1.34-1.30 (m, 4H). LC-MS (Method D): m/z=404.2 [M+H]⁺, 1.872 min.

Example 74:(S)-4-fluoro-N-(5-methyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepin-3-yl)-1-(pyridin-2-ylmethyl)-1H-pyrazole-3-carboxamide

The crude product obtained using Amide Coupling Procedure C was purifiedby Prep-HPLC with the following conditions: Column: X Bridge Prep C18OBD Column, 5 μm, 19×150 mm; Mobile Phase A: water (10 mmol/L NH₄HCO₃),Mobile Phase B: ACN; Flow rate: 20 mL/min; Gradient: 5% B to 57% B over7 min; UV 254 & 220 nm to afford the title compound. ¹H NMR (400 MHz,DMSO-d₆) δ 8.56 (d, J=4.8 Hz, 1H), 8.36 (dd, J=4.8, 1.6 Hz, 1H), 8.27(d, J=7.6 Hz, 1H), 8.16 (d, J=4.4 Hz, 1H), 7.87-7.77 (m, 1H), 7.70 (dd,J=8.0, 1.6 Hz, 1H), 7.38-7.31 (m, 2H), 7.21 (d, J=8.0 Hz, 1H), 5.47 (s,2H), 4.88-4.80 (m, 1H), 4.71-4.64 (m, 1H), 4.52-4.47 (m, 1H), 3.35 (s,3H). LC-MS (Method V): m/z=397.1 [M+H]⁺, 2.159 min.

Example 75A and 75B:5-benzyl-N-((1aS,2S,8bR)-4-methyl-3-oxo-1,1a,2,3,4,8b-hexahydrocyclopropa[d]pyrido[2,3-b]azepin-2-yl)-4H-1,2,4-triazole-3-carboxamide(75A) and5-benzyl-N-((1aR,2R,8bS)-4-methyl-3-oxo-1,1a,2,3,4,8b-hexahydrocyclopropa[d]pyrido[2,3-b]azepin-2-yl)-4H-1,2,4-triazole-3-carboxamide(75B)

Step 1: Preparation of5-benzyl-N-(cis-4-methyl-3-oxo-1,1a,2,3,4,8b-hexahydrocyclopropa[d]pyrido[2,3-b]azepin-2-yl)-4H-1,2,4-triazole-3-carboxamide

The crude product obtained using Amide Coupling Procedure C was purifiedby Prep-HPLC with the following conditions: column: X bridge Prep C18,19×150 mm, 5 μm; Mobile phase: Phase A: water (10 mmol/L NH₄HCO₃); PhaseB: ACN (20% to 80% over 12 min); Detector, UV 220 & 254 nm to afford thetitle compound (55 mg, 44.3%) as a white solid. LC-MS (Method C):m/z=389.2 [M+H]⁺, 1.111 min.

Step 2: Preparation of5-benzyl-N-((1aR,2R,8bS)-4-methyl-3-oxo-1,1a,2,3,4,8b-hexahydrocyclopropa[d]pyrido[2,3-b]azepin-2-yl)-4H-1,2,4-triazole-3-carboxamide(First Eluting Isomer) and5-benzyl-N-((1aS,2S,8bR)-4-methyl-3-oxo-1,1a,2,3,4,8b-hexahydrocyclopropa[d]pyrido[2,3-b]azepin-2-yl)-4H-1,2,4-triazole-3-carboxamide(Second Eluting Isomer)

The enantiomers of5-benzyl-N-(cis-4-methyl-3-oxo-1,1a,2,3,4,8b-hexahydrocyclopropa[d]pyrido[2,3-b]azepin-2-yl)-4H-1,2,4-triazole-3-carboxamide(55 mg, 0.14 mmol) were separated by Prep-Chiral-HPLC with the followingconditions: Column: Chiralpak IC, 2×25 cm, 5 μm; Mobile Phase A: hexane,Mobile Phase B: EtOH; Flow rate: 19 mL/min; Gradient: 35% B to 35% Bover 18.5 min; UV 220 & 254 nm; RT 1: 13.00 min; RT 2: 15.67 min toafford the title compounds:

Example 75B (first eluting isomer): ¹H NMR (400 MHz, DMSO-d₆) δ 14.37(s, 1H), 8.46 (d, J=7.2 Hz, 1H), 8.40-8.38 (m, 1H), 8.02-7.98 (m, 1H),7.35-7.25 (m, 6H), 4.46 (d, J=7.2 Hz, 1H), 4.16 (s, 2H), 3.30 (s, 3H),2.33-2.26 (m, 1H), 2.05-1.99 (m, 1H), 1.21-1.14 (m, 1H), 1.11-1.04 (m,1H). LC-MS (Method D): m/z=389.2 [M+H]⁺, 1.651 min.

Example 75A (second eluting isomer): ¹H NMR (400 MHz, DMSO-d₆) δ 8.54(d, J=7.2 Hz, 1H), 8.40-8.38 (m, 1H), 8.02-7.98 (m, 1H), 7.38-7.23 (m,6H), 4.46 (d, J=7.2 Hz, 1H), 4.14 (s, 2H), 3.30 (s, 3H), 2.32-2.26 (m,1H), 2.06-1.99 (m, 1H), 1.20-1.15 (m, 1H), 1.10-1.04 (m, 1H). LC-MS(Method D): m/z=389.2 [M+H]⁺, 1.656 min.

Example 76:(S)-1-benzyl-4-fluoro-N-(5-methyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepin-3-yl)-1H-pyrazole-3-carboxamide

The crude product obtained using Amide Coupling Procedure C was purifiedby Prep-HPLC with the following conditions: Column: X Bridge Prep C18OBD Column, 5 μm, 19×150 mm; Mobile Phase A: water (10 mmol/L NH₄HCO₃),Mobile Phase B: ACN; Flow rate: 20 mL/min; Gradient: 32% B to 54% B over7 min; UV 254 & 220 nm to afford the title compound. ¹H NMR (300 MHz,DMSO-d₆) δ 8.37 (dd, J=4.5, 1.5 Hz, 1H), 8.26 (d, J=7.5 Hz, 1H), 8.15(d, J=4.5 Hz, 1H), 7.71 (dd, J=8.1, 1.8 Hz, 1H), 7.43-7.27 (m, 6H), 5.36(s, 2H), 4.90-4.80 (m, 1H), 4.73-4.65 (m, 1H), 4.55-4.48 (m, 1H), 3.36(s, 3H). LC-MS (Method D): m/z=396.1 [M+H]⁺, 1.893 min.

Example 77:(S)—N-(5-methyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepin-3-yl)-5-(1-phenylcyclopropyl)isoxazole-3-carboxamide

Step 1: Preparation of ethyl5-(1-phenylcyclopropyl)isoxazole-3-carboxylate

To a mixture of ethyl 2,4-dioxo-4-(1-phenylcyclopropyl)butanoate (970mg, 3.7 mmol) in ethanol (10 mL) was added hydroxylamine hydrochloride(255 mg, 3.7 mmol). The reaction mixture was heated at reflux andstirred for 4 hours. Upon concentration under reduced pressure, theresidue was purified by column chromatography (ethyl acetate/petroleumether, 1/5) to afford the title compound (260 mg, 27%) as a yellowsolid. LC-MS (Method K): m/z=258.1 [M]⁺, 1.603 min.

Step 2: Preparation of 5-(1-phenylcyclopropyl)isoxazole-3-carboxylicacid

To a solution of ethyl 5-(1-phenylcyclopropyl)isoxazole-3-carboxylate(100 mg, 0.39 mmol) in methanol (3 mL) and water (1 mL) was added sodiumhydroxide (93 mg, 2.33 mmol). The resulting mixture was stirred at roomtemperature overnight, concentrated to dryness and diluted with water(10 mL). The reaction mixture was adjusted to pH=5 with aqueoushydrochloric acid (1 N, 10 mL), and extracted with ethyl acetate (3×10mL). The combined organic layers were washed with brine, dried overanhydrous sodium sulfate, filtered and concentrated under vacuum toafford the title compound (80 mg crude) as a yellow solid. LC-MS (MethodE): m/z=229.9 [M+H]⁺, 0.840 min.

Step 3: Preparation of(S)—N-(5-methyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepin-3-yl)-5-(1-phenylcyclopropyl)isoxazole-3-carboxamide

The crude product obtained using Amide Coupling Procedure C was purifiedby Prep-HPLC with the following conditions: Column: X Bridge Prep C18OBD Column, 5 μm, 19×150 mm; Mobile Phase A: water (10 mmol/L NH₄HCO₃),Mobile Phase B: ACN; Flow rate: 20 mL/min; Gradient: 40% B to 75% B over7 min; UV 254 & 220 nm to afford the title compound. ¹H NMR (300 MHz,DMSO-d₆) δ 8.95 (d, J=8.1 Hz, 1H), 8.37 (dd, J=4.8, 1.5 Hz, 1H), 7.70(dd, J=7.8, 1.5 Hz, 1H), 7.43-7.29 (m, 6H), 6.38 (s, 1H), 4.90-4.80 (m,1H), 4.70-4.62 (m, 1H), 4.55-4.48 (m, 1H), 3.35 (s, 3H), 1.58-1.51 (m,2H), 1.50-1.42 (m, 2H). LC-MS (Method D): m/z=405.1 [M+H]⁺, 2.134 min.

Example 78:(S)—N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-5-(1-phenylcyclopropyl)-1H-imidazole-2-carboxamide

Step 1: Preparation of 2-bromo-1-(1-phenylcyclopropyl)ethanone

To a solution of 1-(1-phenylcyclopropyl)ethanone (4.0 g, 25.0 mmol) andtriethylamine (5.0 g, 50 mmol) in dichloromethane (100 mL) was addedtrimethylsilyl trifluoromethanesulfonate (5.55 g, 25.0 mmol) at 0° C.After stirring for 0.5 hour, 1-bromopyrrolidine-2,5-dione (4.9 g, 27.5mmol) was added in portions at 0° C. The reaction mixture was stirredfor another 2 hours, quenched with 100 mL of water and extracted withdichloromethane (3×80 mL). The combined organic phases were washed withbrine, dried over sodium sulfate, filtered and concentrated undervacuum. The residue was purified by column chromatography (ethylacetate/petroleum ether, 1/20) to afford the title compound (3.4 g, 57%)as a yellow oil. LC-MS (Method E): m/z=238.8 [M+H]⁺, 0.971 min.

Step 2: Preparation of ethyl5-(1-phenylcyclopropyl)-1H-imidazole-2-carboxylate

A solution of 2-bromo-1-(1-phenylcyclopropyl)ethanone (3.4 g, 14.2mmol), ethyl 2-amino-2-iminoacetate (1.65 g, 14.2 mmol) andtriethylamine (4.3 g, 42.6 mmol) in ethanol (50 mL) was heated at refluxfor 5 hours. Upon concentration under reduced pressure the resultingresidue was purified by column chromatography (ethyl acetate/petroleumether, 1/5) to afford the title compound (520 mg, 14%) as a yellowsolid. LC-MS (Method C): m/z=257.0 [M+H]⁺, 1.000 min.

Step 3: Preparation of 5-(1-phenylcyclopropyl)-1H-imidazole-2-carboxylicacid

To a solution of ethyl5-(1-phenylcyclopropyl)-1H-imidazole-2-carboxylate (300 mg, 1.2 mmol) inmethanol (9 mL) and water (3 mL) was added sodium hydroxide (288 mg, 7.2mmol). The mixture was stirred at room temperature overnight. Thesolution was adjusted to pH=5, and extracted with ethyl acetate (3×10mL). The combined organic layers were washed with brine, dried overanhydrous sodium sulfate and concentrated under vacuum to afford thetitle compound (130 mg crude) as a yellow solid. LC-MS (Method C):m/z=229.1 [M+H]⁺, 0.906 min.

Step 4: Preparation of(S)—N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-5-(1-phenylcyclopropyl)-1H-imidazole-2-carboxamide

The crude product obtained using Amide Coupling Procedure C was purifiedby Prep-HPLC with the following conditions: Column: XBridge Prep C18 OBDColumn, 5 μm, 19×150 mm; mobile phase, water (10 mmol/L NH₄HCO₃), ACN(40% ACN to 70% B over 7 min); detector, UV 254 & 220 nm to afford thetitle compound. ¹H NMR (400 MHz, DMSO-d₆) δ 13.11-12.79 (m, 1H),8.32-8.17 (m, 1H), 7.51 (dd, J=7.6, 1.9 Hz, 1H), 7.37-7.16 (m, 8H),6.85-6.44 (m, 1H), 4.88-4.74 (m, 1H), 4.66-4.50 (m, 1H), 4.45-4.35 (m,1H), 3.32 (s, 3H), 1.38-1.27 (m, 2H), 1.25-1.12 (m, 2H). LC-MS (MethodQ): m/z=403.3 [M+H]⁺, 1.533 min.

Example 79:(S)-7-(2-fluorophenyl)-N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)benzo[d]thiazole-2-carboxamide

Step 1: Preparation of(S)-7-bromo-N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)benzo[d]thiazole-2-carboxamide

Utilizing the procedure described in Example 54 provided title compound(370 mg) as a yellow solid that was used in the next step withoutpurification. LC-MS (Method S): m/z=432.2 [M+H]⁺, 1.102 min.

Step 2: Preparation of7-(2-fluorophenyl)-N—((S)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)benzo[d]thiazole-2-carboxamide

[1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) (29 mg, 0.04mmol) was added to a mixture of(S)-7-bromo-N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxaz-epin-3-yl)benzo[d]thiazole-2-carboxamide(170 mg, 0.39 mmol), 2-fluorophenylboronic acid (85 mg, 0.59 mmol) andpotassium carbonate (109 mg, 0.79 mmol) in dioxane (2 mL) and water (0.5mL) under an atmosphere of nitrogen. The resulting mixture was stirredovernight at 80° C. Solids were removed by filtration and the filtratewas concentrated under reduced pressure. The residue was purified byPrep-HPLC with the following conditions: Column: XBridge Prep C18 OBDColumn, 5 μm, 19×150 mm; Mobile Phase A: water (0.05% TFA), Mobile PhaseB: ACN; Flow rate: 20 mL/min; Gradient: 3% B to 38% B over 7 min; 254 &220 nm; Rt: 6.33 min to afford the title compound. ¹H NMR (300 MHz,DMSO-d₆) δ 9.31-9.29 (d, J=7.5 Hz, 1H), 8.29-8.26 (d, J=8.1 Hz, 1H),7.79-7.77 (m, 1H), 7.68-7.60 (m, 2H), 7.60-7.51 (m, 2H), 7.43-7.26 (m,5H), 4.89-4.72 (m, 2H), 4.50-4.44 (m, 1H), 3.33 (s, 3H). LC-MS (MethodT): m/z=448.3 [M+H]⁺, 1.884 min.

Example 80A and 80B:5-benzyl-N-((1aS,2S,8bR)-4-methyl-3-oxo-1,1a,2,3,4,8b-hexahydrocyclopropa[d]pyrido[2,3-b]azepin-2-yl)-1H-pyrazole-3-carboxamide(80A) and5-benzyl-N-((1aR,2R,8bS)-4-methyl-3-oxo-1,1a,2,3,4,8b-hexahydrocyclopropa[d]pyrido[2,3-b]azepin-2-yl)-1H-pyrazole-3-carboxamide(80B)

Step 1: Preparation of5-benzyl-N-(cis-4-methyl-3-oxo-1,1a,2,3,4,8b-hexahydrocyclopropa[d]pyrido[2,3-b]azepin-2-yl)-1H-pyrazole-3-carboxamide

The crude product obtained using Amide Coupling Procedure C was purifiedby Prep-HPLC with the following conditions: Column: X Bridge C18 OBDPrep Column, 100 Å, 5 μm, 19 mm×250 mm; Mobile Phase A: water (10 mmol/LNH₄HCO₃), Mobile Phase B: ACN; Flow rate: 20 mL/min; Gradient: 30% B to50% B over 7 min; UV 254 & 220 nm to afford the title compound. LC-MS(Method D): m/z=388.2 [M+H]⁺, 1.757 min.

Step 2: Preparation of5-benzyl-N-((1aS,2S,8bR)-4-methyl-3-oxo-1,1a,2,3,4,8b-hexahydrocyclopropa[d]pyrido[2,3-b]azepin-2-yl)-1H-pyrazole-3-carboxamide (FirstEluting Isomer) and5-benzyl-N-((1aR,2R,8bS)-4-methyl-3-oxo-1,1a,2,3,4,8b-hexahydrocyclopropa[d]pyrido[2,3-b]azepin-2-yl)-1H-pyrazole-3-carboxamide(Second Eluting Isomer)

The racemate of5-benzyl-N-(cis-4-methyl-3-oxo-1,1a,2,3,4,8b-hexahydrocyclopropa[d]pyrido[2,3-b]azepin-2-yl)-1H-pyrazole-3-carboxamide(60 mg, 0.16 mmol) was separated by Prep-Chiral-HPLC with the followingconditions: Column: CHIRAL IC, 2×25 cm, 5 μm; Mobile Phase A: hexane,Mobile Phase B: EtOH; Flow rate: 20 mL/min; Gradient: 60% B to 60% Bover 16.5 min; UV 254 & 220 nm; RT 1: 8.27 min; RT 2: 13.00 min toafford the title compounds:

Example 80A (first eluting isomer): ¹H NMR (300 MHz, Methanol-d₄) δ 8.38(dd, J=4.8, 1.8 Hz, 1H), 7.94 (dd, J=7.8, 1.8 Hz, 1H), 7.35-7.21 (m,6H), 6.52 (s, 1H), 4.65 (s, 1H), 4.05 (s, 2H), 3.40 (s, 3H), 2.31-2.23(m, 1H), 2.12-2.03 (m, 1H), 1.32-1.26 (m, 1H), 1.22-1.13 (m, 1H). LC-MS(Method D): m/z=388.2 [M+H]⁺, 1.757 min.

Example 80B (second eluting isomer): ¹H NMR (300 MHz, Methanol-d₄) δ8.38 (dd, J=4.5, 1.8 Hz, 1H), 7.94 (dd, J=7.8, 1.5 Hz, 1H), 7.35-7.21(m, 6H), 6.52 (s, 1H), 4.65 (s, 1H), 4.06 (s, 2H), 3.40 (s, 3H),2.31-2.23 (m, 1H), 2.12-2.04 (m, 1H), 1.33-1.26 (m, 1H), 1.22-1.13 (m,1H). LC-MS (Method D): m/z=388.2 [M+H]⁺, 1.757 min.

Example 81A and 81B:5-benzyl-N-((1aS,2S,8bR)-4-methyl-3-oxo-1,1a,2,3,4,8b-hexahydrocyclopropa[d]pyrido[2,3-b]azepin-2-yl)isoxazole-3-carboxamide(81A) and5-benzyl-N-((1aR,2R,8bS)-4-methyl-3-oxo-1,1a,2,3,4,8b-hexahydrocyclopropa[d]pyrido[2,3-b]azepin-2-yl)isoxazole-3-carboxamide(81B)

Step 1: Preparation of5-benzyl-N-(cis-4-methyl-3-oxo-1,1a,2,3,4,8b-hexahydrocyclopropa[d]pyrido[2,3-b]azepin-2-yl)isoxazole-3-carboxamide

The crude product obtained using Amide Coupling Procedure C was purifiedby Prep-HPLC with the following conditions: Column: X Bridge Prep C18OBD Column, 5 μm, 19×150 mm; Mobile Phase A: water (10 mmol/L NH₄HCO₃),Mobile Phase B: ACN; Flow rate: 20 mL/min; Gradient: 25% B to 55% B over7 min; UV 254 & 220 nm to afford the title compound. LC-MS (Method D):m/z=389.1 [M+H]⁺, 2.036 min.

Step 2: Preparation of5-benzyl-N-((1aR,2R,8bS)-4-methyl-3-oxo-1,1a,2,3,4,8b-hexahydrocyclopropa[d]pyrido[2,3-b]azepin-2-yl)isoxazole-3-carboxamide(First Eluting Isomer) and5-benzyl-N-((1aS,2S,8bR)-4-methyl-3-oxo-1,1a,2,3,4,8b-hexahydrocyclopropa[d]pyrido[2,3-b]azepin-2-yl)isoxazole-3-carboxamide(Second Eluting Isomer)

The racemate of5-benzyl-N-(cis-4-methyl-3-oxo-1,1a,2,3,4,8b-hexahydrocyclopropa[d]pyrido[2,3-b]azepin-2-yl)isoxazole-3-carboxamide(60 mg, 0.15 mmol) was separated by Prep-Chiral-HPLC with the followingconditions: Column: Chiralpak IC, 2×25 cm, 5 μm; Mobile Phase A:hexanes, Mobile Phase B: EtOH; Flow rate: 18 mL/min; Gradient: 50% B to50% B over 17 min; UV 254 & 220 nm; RT 1:12.098 min; RT 2: 14.358 min toafford the title compounds:

Example 81B (first eluting isomer): ¹H NMR (300 MHz, DMSO-d₆) δ 8.98 (d,J=7.5 Hz, 1H), 8.40 (dd, J=4.5, 1.8 Hz, 1H), 7.98 (dd, J=7.5, 1.8 Hz,1H), 7.40-7.26 (m, 6H), 6.62 (s, 1H), 4.45 (d, J=7.2 Hz, 1H), 4.24 (s,2H), 3.29 (s, 3H), 2.34-2.25 (m, 1H), 2.02-1.94 (m, 1H), 1.25-1.06 (m,2H). LC-MS (Method D): m/z=389.1 [M+H]⁺, 2.036 min.

Example 81A (second eluting isomer): ¹H NMR (300 MHz, DMSO-d₆) δ 8.98(d, J=7.2 Hz, 1H), 8.40 (dd, J=4.5, 1.8 Hz, 1H), 7.98 (dd, J=7.5, 1.8Hz, 1H), 7.40-7.26 (m, 6H), 6.62 (s, 1H), 4.45 (d, J=7.2 Hz, 1H), 4.24(s, 2H), 3.29 (s, 3H), 2.34-2.25 (m, 1H), 2.02-1.94 (m, 1H), 1.22-1.06(m, 2H). LC-MS (Method D): m/z=389.1 [M+H]⁺, 2.027 min.

Example 82A and 82B:1-benzyl-4-fluoro-N-((1aS,2S,8bR)-4-methyl-3-oxo-1,1a,2,3,4,8b-hexahydrocyclopropa[d]pyrido[2,3-b]azepin-2-yl)-1H-pyrazole-3-carboxamide(82A) and1-benzyl-4-fluoro-N-((1aR,2R,8bS)-4-methyl-3-oxo-1,1a,2,3,4,8b-hexahydrocyclopropa[d]pyrido[2,3-b]azepin-2-yl)-1H-pyrazole-3-carboxamide(82B)

Step 1: Preparation of1-benzyl-4-fluoro-N-(cis-4-methyl-3-oxo-1,1a,2,3,4,8b-hexahydrocyclopropa[d]pyrido[2,3-b]azepin-2-yl)-1H-pyrazole-3-carboxamide

The crude product obtained using Amide Coupling Procedure C was purifiedby Prep-HPLC with the following conditions: Column: X Bridge C18 OBDPrep Column, 100 Å, 5 μm, 19 mm×250 mm; Mobile Phase A: water (10 mmol/LNH₄HCO₃), Mobile Phase B: ACN; Flow rate: 20 mL/min; Gradient: 35% B to65% B over 7 min; UV 254 & 220 nm to afford the title compound (58 mg,50%) as a white solid. LC-MS (Method V): m/z=406.1 [M+H]⁺, 2.852 min.

Step 2: Preparation of1-benzyl-4-fluoro-N-((1aR,2R,8bS)-4-methyl-3-oxo-1,1a,2,3,4,8b-hexahydrocyclopropa[d]pyrido[2,3-b]azepin-2-yl)-1H-pyrazole-3-carboxamide(First Eluting Isomer) and1-benzyl-4-fluoro-N-((1aS,2S,8bR)-4-methyl-3-oxo-1,1a,2,3,4,8b-hexahydrocyclopropa[d]pyrido[2,3-b]azepin-2-yl)-1H-pyrazole-3-carboxamide(Second Eluting Isomer)

The racemate of1-benzyl-4-fluoro-N-(cis-4-methyl-3-oxo-1,1a,2,3,4,8b-hexahydrocyclopropa[d]pyrido[2,3-b]azepin-2-yl)-1H-pyrazole-3-carboxamide(58 mg, 0.15 mmol) was separated by Prep-Chiral-HPLC with the followingconditions: Column: Chiralpak IC, 2×25 cm, 5 μm; Mobile Phase A: hexane,Mobile Phase B: EtOH; Flow rate: 18 mL/min; Gradient: 50% B to 50% Bover 23 min; UV 254 & 220 nm; RT 1: 10.936 min; RT 2: 16.976 min toafford the title compounds:

Example 82B (first eluting isomer): ¹H NMR (300 MHz, DMSO-d₆) δ 8.39(dd, J=4.8, 1.8 Hz, 1H), 8.17-8.12 (m, 2H), 8.00 (dd, J=7.8, 1.8 Hz,1H), 7.44-7.28 (m, 6H), 5.36 (s, 2H), 4.46 (d, J=6.9 Hz, 1H), 3.30 (s,3H), 2.33-2.24 (m, 1H), 2.06-1.98 (m, 1H), 1.26-1.14 (m, 1H), 1.12-1.03(m, 1H). LC-MS (Method V): m/z=406.1 [M+H]⁺, 2.852 min.

Example 82A (second eluting isomer): ¹H NMR (300 MHz, Methanol-d₄) δ8.38 (dd, J=4.8, 1.8 Hz, 1H), 7.94 (dd, J=7.5, 1.8 Hz, 1H), 7.77 (d,J=4.5 Hz, 1H), 7.44-7.27 (m, 6H), 5.35 (s, 2H), 4.66 (s, 1H), 3.41 (s,3H), 2.32-2.23 (m, 1H), 2.15-2.03 (m, 1H), 1.33-1.26 (m, 1H), 1.22-1.14(m, 1H). LC-MS (Method D): m/z=406.1 [M+H]⁺, 1.932 min.

Example 83A:5-benzyl-N-((1aS,2S,8bR)-5,7-difluoro-3-oxo-1,1a,2,3,4,8b-hexahydrobenzo[b]cyclopropa[d]azepin-2-yl)-4H-1,2,4-triazole-3-carboxamide

Step 1: Preparation of 2,4-difluoro-6-vinylbenzenamine

To a solution of 2-bromo-4,6-difluoroaniline (10.0 g, 48.0 mmol) inN,N-dimethylformamide (50 mL) was added tributyl(ethenyl)stannane (18.0g, 56.7 mmol) and tetrakis(triphenylphosphine)palladium (2.2 g, 1.90mmol) under a nitrogen atmosphere. The resulting mixture was stirred for16 hours at 80° C. After cooling to room temperature, the reactionmixture was quenched by the addition of water (200 mL) and extractedwith dichloromethane (3×200 mL). The combined organic layers were washedwith brine, dried over sodium sulfate, filtered and concentrated undervacuum. The residue was purified by column chromatography (ethylacetate/petroleum ether, 3/17) to afford the title compound (6.0 g, 80%)as a yellow oil. LC-MS (Method C): m/z=156.0 [M+H]⁺, 1.216 min.

Step 2: Preparation of N-(2,4-difluoro-6-vinylphenyl)but-3-enamide

Thionyl chloride (9.3 g, 46.46 mmol) was added to a solution ofbut-3-enoic acid (4.0 g, 46.46 mmol) in dichloromethane (20 mL)dropwise. After stirring for 1 hour at room temperature, the resultingmixture was added to a solution of triethylamine (11.8 g, 116.6 mmol)and 2-ethenyl-4,6-difluoroaniline (6.0 g, 38.67 mmol) in dichloromethane(20 mL). The reaction mixture was stirred for 3 hours at roomtemperature, quenched by the addition of water (50 mL) and extractedwith dichloromethane (3×100 mL). The combined organic layers were washedwith brine, dried over sodium sulfate, filtered and concentrated undervacuum. The residue was purified by column chromatography (ethylacetate/petroleum ether, 3/17) to afford the title compound (5.7 g, 66%)as a yellow oil. LC-MS (Method C): m/z=224.0 [M+H]⁺, 1.145 min.

Step 3: Preparation of (Z)-7,9-difluoro-1H-benzo[b]azepin-2(3H)-one

[1,3-bis(2,4,6-trimethylphenyl)imidazolidin-2-ylidene]dichloro(phenylmethylidene)ruthenium tricyclohexylphosphine (3.4 g, 4.0 mmol) was added to asolution of N-(5-ethenyl-2,4-difluorophenyl)but-3-enamide (4.4 g, 19.9mmol) in toluene (150 mL). The resulting solution was stirred for 16hours at 80° C. and then concentrated under vacuum. The residue waspurified by column chromatography (ethyl acetate/petroleum ether, 1/4)to afford the title compound (2.8 g, 69%) as a yellow oil. LC-MS (MethodS): m/z=196.0 [M+H]⁺, 0.754 min.

Step 4: Preparation of5,7-difluoro-1,1a,2,8b-tetrahydrobenzo[b]cyclopropa[d]azepin-3(4H)-one

To a solution of potassium hydroxide (40 g, 714 mmol) in water (60 mL)was added a solution of 1-methyl-1-nitrosourea (20.6 g, 199.8 mmol) inether (150 mL) dropwise at 0° C. under nitrogen atmosphere. Theresulting mixture was stirred for 1 hour at 0° C. and then the organicphase was separated to get a solution of diazomethane (150 mL). To asolution of 7,9-difluoro-2,3-dihydro-1H-1-benza-zepin-2-one (2.0 g,10.25 mmol) in tetrahydrofuran (60 mL) was added the solution ofdiazomethane (150 mL) dropwise, followed by adding a mixture ofpalladium diacetate (224.5 mg, 1.00 mmol) in tetrahydrofuran (10 mL)dropwise at 0° C. The reaction mixture was stirred overnight at roomtemperature. The solids were removed by filtration and the filtrate wasconcentrated under vacuum to afford the title compound (1.2 g crude) asa yellow oil. LC-MS (Method C): m/z=210.0 [M+H]⁺, 1.117 min.

Step 5: Preparation oftrans-5,7-difluoro-2-iodo-1,1a,2,8b-tetrahydrobenzo[b]cyclopropa[d]azepin-3(4H)-one

To a mixture of5,7-difluoro-1,1a,2,8b-tetrahydrobenzo[b]cyclopropa[d]azepin-3(4H)-one(1.2 g, 6.0 mmol) in dichloromethane (60 mL) was addedN,N,N′,N′-tetramethylethylenediamine (2.1 g, 18.0 mmol) followed by theaddition of iodotrimethylsilane (3.6 g, 18.0 mmol) at 0° C. Afterstirring for 2 hours at 0° C., iodine (2.3 g, 9.0 mmol) was added. Thereaction mixture was stirred for 1 hour at 0° C., quenched with aqueoussodium thiosulfate (5%, 40 mL) and extracted with ethyl acetate (3×50mL). The combined organic layers were washed with brine, dried overanhydrous sodium sulfate, and filtered. The filtrate was concentratedunder vacuum to afford the title compound (1.32 g crude) as a yellowoil. LC-MS (Method C): m/z=336.0 [M+H]⁺, 1.213 min.

Step 6: Preparation ofcis-2-azido-5,7-difluoro-1,1a,2,8b-tetrahydrobenzo[b]cyclopropa[d]azepin-3(4H)-one

Sodium azide (250 mg, 3.84 mmol) was added to a solution oftrans-5,7-difluoro-2-iodo-1,1a,2,8b-tetrahydrobenzo[b]cyclopropa[d]azepin-3(4H)-one(860 mg, 2.56 mmol) in N,N-dimethylformamide (40 mL). The resultingmixture was stirred for 16 hours at room temperature, quenched by addingwater (50 mL) and extracted with ethyl acetate (3×50 mL). The combinedorganic layers were washed with brine, dried over sodium sulfate, andfiltered. The filtrate was concentrated under vacuum to afford the titlecompound (520 mg crude) as a yellow oil. LC-MS (Method C): m/z=251.0[M+H]⁺, 1.176 min.

Step 7. Preparation ofcis-2-amino-5,7-difluoro-1,1a,2,8b-tetrahydrobenzo[b]cyclopropa[d]azepin-3(4H)-one

Triphenylphosphine (629 mg, 2.40 mmol) was added to a solution ofcis-2-azido-5,7-difluoro-1,1a,2,8b-tetrahydrobenzo[b]cyclopropa[d]azepin-3(4H)-one(400 mg, 1.60 mmol) in tetrahydrofuran (10 mL) and water (1 mL). Theresulting mixture was stirred for 16 hours at room temperature, dilutedwith water (50 mL) and extracted with dichloromethane (3×50 mL). Thecombined organic layers were washed with brine, dried over anhydroussodium sulfate, filtered and concentrated to dryness under vacuum. Theresidue was purified by column chromatography (methanol/dichloromethane,3/97) to afford the title compound (310 mg, 86%) as a yellow oil. LC-MS(Method C): m/z=225.0 [M+H]⁺, 0.776 min.

Step 8: Preparation of(1aR,2R,8bS)-2-amino-5,7-difluoro-1,1a,2,8b-tetrahydrobenzo[b]cyclopropa[d]azepin-3(4H)-one(First Eluting Isomer) and(aS,2S,8bR)-2-amino-5,7-difluoro-1,1a,2,8b-tetrahydrobenzo[b]cyclopropa[d]azepin-3(4H)-one(Second Eluting Isomer)

The racemate ofcis-2-amino-5,7-difluoro-1,1a,2,8b-tetrahydrobenzo[b]cyclopropa[d]azepin-3(4H)-one (310 mg, 1.38 mmol) was separated by Prep-Chiral-HPLCwith the following conditions: Column: Chiralpak IA, 2×25 cm, 5 μm;Mobile Phase A: hexane, Mobile Phase B: EtOH; Flow rate: 15 mL/min;Gradient: 50% B to 50% B over 28 min; 254/220 nm; RT1: 10.247 min; RT2:20.789 min to afford the title compounds:

(1aR,2R,8bS)-2-amino-5,7-difluoro-1,1a,2,8b-tetrahydrobenzo[b]cyclopropa[d]azepin-3(4H)-one (first eluting isomer): (150 mg, 48%) as a white solid.LC-MS (Method C): m/z=225.0 [M+H]⁺, 0.776 min.

(1aS,2S,8bR)-2-amino-5,7-difluoro-1,1a,2,8b-tetrahydrobenzo[b]cyclopropa[d]azepin-3(4H)-one (second eluting isomer): (140 mg, 45%) as a whitesolid. LC-MS (Method C): m/z=225.0 [M+H]⁺, 0.776 min.

Step 9:5-benzyl-N-((1aS,2S,8bR)-5,7-difluoro-3-oxo-1,1a,2,3,4,8b-hexahydrobenzo[b]cyclopropa[d]azepin-2-yl)-4H-1,2,4-triazole-3-carboxamide

N,N-diisopropylethylamine (50 mg, 0.39 mmol) was added to a mixture of(aS,2S,8bR)-2-amino-5,7-difluoro-1,1a,2,8b-tetrahydrobenzo[b]cyclopropa[d]azepin-3(4H)-one(30 mg, 0.13 mmol), 5-benzyl-4H-1,2,4-triazole-3-carboxylic acid (32 mg,0.16 mmol), N-(3-dimethylaminopropyl)-N′-ethylcarbodimide hydrochloride(31 mg, 0.16 mmol) and 1-hydroxybenzotriazole (22 mg, 0.16 mmol) inN,N-dimethylformamide (5 mL). The resulting mixture was stirred for 2hours at room temperature, diluted with water (50 mL) and extracted withethyl acetate (3×50 mL). The combined organic layers were washed withbrine, dried over sodium sulfate, filtered and concentrated undervacuum. The residue was purified by Prep-HPLC with the followingconditions: Column, XBridge C18 OBD Prep Column, 5 μm, 19 mm×250 mm;mobile phase, water (10 mmoL/L NH₄HCO₃) and ACN (30.0% ACN to 60.0% over7 min); Detector, UV 254 nm to afford the title compound. ¹H NMR (400MHz, DMSO-d₆) δ 14.30 (br. s, 1H), 9.96 (br. s, 1H), 8.43 (d, J=6.8 Hz,1H), 7.36-7.19 (m, 7H), 4.61 (d, J=6.8 Hz, 1H), 4.14 (s, 2H), 2.32-2.26(m, 1H), 2.07-2.01 (m, 1H), 1.43-1.39 (m, 1H), 1.12-1.07 (m, 1H). LC-MS(Method Q): m/z=410.3 [M+H]⁺, 1.144 min.

Example 83B:5-benzyl-N-((1aR,2R,8bS)-5,7-difluoro-3-oxo-1,1a,2,3,4,8b-hexahydrobenzo[b]cyclopropa[d]azepin-2-yl)-4H-1,2,4-triazole-3-carboxamide

The crude product obtained using Amide Coupling Procedure C was purifiedby Prep-HPLC with the following conditions: Column, XBridge C18 OBD PrepColumn, 5 μm, 19 mm×250 mm; mobile phase, water (10 mmoL/L NH₄HCO₃) andACN (30.0% ACN up to 60.0% in 7 min); Detector, UV 254 nm to afford thetitle compound. ¹H NMR (400 MHz, DMSO-d₆) δ 14.41 (s, 1H), 9.95 (s, 1H),8.42 (d, J=6.8 Hz, 1H), 7.35-7.19 (m, 7H), 4.61 (d, J=6.8 Hz, 1H), 4.14(s, 2H), 2.32-2.26 (m, 1H), 2.07-2.01 (m, 1H), 1.43-1.39 (m, 1H),1.12-1.07 (m, 1H). LC-MS (Method Q): m/z=410.30 [M+H]⁺, 1.143 min.

Example 84:(S)—N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-7-phenylbenzo[d]thiazole-2-carboxamide

[1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) (34 mg, 0.05mmol) was added to a mixture of(S)-7-bromo-N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxaz-epin-3-yl)benzo[d]thiazole-2-carboxamide(200 mg, 0.47 mmol), phenylboronic acid (85 mg, 0.70 mmol) and potassiumcarbonate (128 mg, 0.93 mmol) in dioxane (2 mL) and water (0.5 mL) undera nitrogen atmosphere. The resulting mixture was stirred overnight at80° C. Solids were removed by filtration and the filtrate wasconcentrated under reduced pressure. The residue was purified byPrep-HPLC with the following conditions: Column: XBridge Prep C18 OBDColumn, 5 μm, 19×150 mm; Mobile Phase A: water (0.05% TFA), Mobile PhaseB: ACN; Flow rate: 20 mL/min; Gradient: 3% B to 38% B over 7 min; 254 &220 nm; Rt: 6.33 min to afford the title compound. ¹H NMR (300 MHz,DMSO-d₆) δ 9.30 (d, J=7.8 Hz, 1H), 8.23 (d, J=7.8 Hz, 1H), 7.79-7.60 (m,4H), 7.60-7.49 (m, 4H), 7.34-7.26 (m, 3H), 4.96-4.68 (m, 2H), 4.50-4.45(m, 1H), 3.33 (s, 3H). LC-MS (Method T): m/z=430.3 [M+H]⁺, 1.906 min.

Example 85:(S)-5-benzyl-N-(5-methyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepin-3-yl)-1,3,4-thiadiazole-2-carboxamide

Step 1: Preparation of ethyl2-oxo-2-(2-(2-phenylacetyl)hydrazinyl)acetate

To a stirring solution of 2-phenylacetohydrazide (2 g, 13.3 mmol) andtriethylamine (4.04 g, 39.9 mmol) in dichloromethane (30 mL) was addedethyl 2-chloro-2-oxoacetate (1.8 g, 13.4 mmol) dropwise at 0° C. Theresulting solution was stirred for 12 hours at room temperature, dilutedwith water (20 mL) and extracted with dichloromethane (5×50 mL). Thecombined organic layers were washed with brine, dried over anhydroussodium sulfate, filtered and concentrated under vacuum. The residue waspurified by column chromatography (ethyl acetate/petroleum ether, 1/3)to afford the title compound (1.2 g, 36%) as a white solid. LC-MS(Method I): m/z=251.0[M+H]⁺, 0.944 min.

Step 2: Preparation of ethyl 5-benzyl-1,3,4-thiadiazole-2-carboxylate

To a mixture of ethyl 2-oxo-2-(2-(2-phenylacetyl)hydrazinyl)acetate(0.65 g, 2.6 mmol) in tetrahydrofuran (8 mL) was added Lawesson'sreagent (1.89 g, 4.7 mmol). The resulting mixture was stirred for 3hours at 70° C. After cooling to room temperature, the reaction mixturewas diluted with ethyl acetate (30 mL). The phases were separated andthe organic layer was washed with aqueous sodium bicarbonate (10%, 3×20mL) and brine, dried over anhydrous sodium sulfate, filtered andconcentrated to dryness under vacuum. The residue was purified by columnchromatography (ethyl acetate/petroleum ether, 1/3) to afford the titlecompound (500 mg, 78%) as a yellow oil. LC-MS (Method I): m/z=249.0[M+H]⁺, 0.991 min.

Step 3: Preparation of 5-benzyl-1,3,4-thiadiazole-2-carboxylic acid

To a mixture of ethyl 5-benzyl-1,3,4-thiadiazole-2-carboxylate (500 mg,2.01 mmol) in tetrahydrofuran (6 mL) and water (2 mL) was added lithiumhydroxide (97 mg, 4.04 mmol). The resulting solution was stirred for 12hours at room temperature and concentrated under vacuum. The residue wasdiluted with water (10 mL) and the pH value of the solution was adjustedto 6 with aqueous hydrochloric acid (1 N, 10 mL). The resulting solutionwas extracted with ethyl acetate (3×15 mL). The combined organic layerswere washed with brine, dried over anhydrous sodium sulfate, andfiltered. The filtrate was concentrated under vacuum to afford the titlecompound (250 mg crude) as a white solid. LC-MS (Method I): m/z=221.0[M+H]⁺, 0.574 min.

Step 4: Preparation of(S)-5-benzyl-N-(5-methyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepin-3-yl)-1,3,4-thiadiazole-2-carboxamide

The crude product obtained using Amide Coupling Procedure C was purifiedby Prep-HPLC with the following conditions: Column: X Bridge Prep C18OBD Column, 5 μm, 19×150 mm; Mobile Phase A: water (10 mmol/L NH₄HCO₃),Mobile Phase B: ACN; Flow rate: 20 mL/min; Gradient: 38% B to 70% B over7 min; UV 254 & 220 nm to afford the title compound. ¹H NMR (300 MHz,DMSO-d₆) δ 9.46 (d, J=6.6 Hz, 1H), 8.37 (dd, J=4.8, 1.8 Hz, 1H), 7.71(dd, J=7.8, 1.5 Hz, 1H), 7.38-7.26 (m, 6H), 4.91-4.75 (m, 2H), 4.58-4.52(m, 3H), 3.36 (s, 3H). LC-MS (Method D): m/z=396.1 [M+H]⁺, 1.912 min.

Example 86:(S)-5-benzyl-N-(5-methyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepin-3-yl)thiazole-2-carboxamide

The crude product obtained using Amide Coupling Procedure C was purifiedby Prep-HPLC with the following conditions: Column: X Bridge Prep C18OBD Column, 5 μm, 19×150 mm; Mobile Phase A: water (10 mmol/L NH₄HCO₃),Mobile Phase B: ACN; Flow rate: 20 mL/min; Gradient: 38% B to 70% B over7 min; UV 254 & 220 nm to afford the title compound. ¹H NMR (300 MHz,DMSO-d₆) δ 8.95 (d, J=7.2 Hz, 1H), 8.37 (dd, J=4.8, 1.5 Hz, 1H), 7.88(s, 1H), 7.71 (dd, J=8.1, 1.5 Hz, 1H), 7.37-7.23 (m, 6H), 4.89-4.72 (m,2H), 4.56-4.50 (m, 1H), 4.28 (s, 2H), 3.36 (s, 3H). LC-MS (Method D):m/z=395.1 [M+H]⁺, 2.096 min.

Example 87:(S)—N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1-(1-phenylcyclopropyl)-1H-1,2,3-triazole-4-carboxamide

Step 1: Preparation of tert-butyl 1-phenylcyclopropylcarbamate

To a stirring mixture of 1-phenylcyclopropanecarboxylic acid (10.0 g,61.7 mmol) and diphenyl phosphorazidate (17.0 g, 61.7 mmol) in toluene(100 mL) was added triethylamine (18.6 g, 185 mmol). The reactionmixture was stirred for 5 hours at 100° C., cooled to room temperatureand then 2-methylpropan-2-ol (33.7 mg, 0.216 mmol) was added. Thereaction mixture was stirred overnight at room temperature andconcentrated under high vacuum. The residue was diluted with water (100mL) and extracted with ethyl acetate (3×100 mL). The combined organiclayers were washed with brine, dried over anhydrous sodium sulfate,filtered and concentrated under vacuum. The residue was purified bycolumn chromatography (ethyl acetate/petroleum ether, 1/5) to afford thetitle compound (4.00 g, 28%) as a yellow solid. LC-MS (Method C):m/z=234.2 [M+H]⁺, 1.345 min.

Step 2: Preparation of 1-phenylcyclopropanamine hydrochloride

Tert-butyl 1-phenylcyclopropylcarbamate (4.0 g, 17.2 mmol) was added toa solution of hydrogen chloride in dioxane (4 N, 50 mL, 200 mmol). Thereaction mixture was stirred for 3 hours at room temperature andconcentrated under high vacuum to afford the title compound (2.00 g,88%) as a white solid. LC-MS (Method C): m/z=134.2 [M+H]⁺, 0.775 min.

Step 3: Preparation of (1-azidocyclopropyl)benzene

To a stirring solution of 1-phenylcyclopropanamine hydrochloride (320mg, 1.89 mmol) in ether (10 mL) was added a solution of methylmagnesiumbromide in ether (3 M, 1.89 mL, 5.67 mmol) at −60° C. under an argonatmosphere. After stirring for 30 minutes at −60° C.,4-methylbenzenesulfonyl azide (745 mg, 3.78 mmol) was added. Thereaction mixture was stirred for 1 hour at −60° C., quenched with water(20 mL) and extracted with ethyl acetate (3×20 mL). The combined organiclayers were washed with brine, dried over anhydrous sodium sulfate, andfiltered. The filtrate was concentrated under vacuum to afford the titlecompound (500 mg crude) as a yellow solid.

Step 4: Preparation of ethyl1-(1-phenylcyclopropyl)-1H-1,2,3-triazole-4-carboxylate

Cupric acetate (468 mg, 3.14 mmol) was added to a solution of(1-azidocyclopropyl)benzene in ethyl propiolate (5 mL). The reactionmixture was stirred overnight at room temperature and concentrated underhigh vacuum. The residue was purified by column chromatography (ethylacetate/petroleum ether, 1/3) to afford the title compound (100 mg, 12%)as a yellow oil. LC-MS (Method C): m/z=258.1 [M+H]⁺, 1.250 min.

Step 5: Preparation of1-(1-phenylcyclopropyl)-1H-1,2,3-triazole-4-carboxylic acid

Lithium hydroxide (18.7 mg, 0.78 mmol) was added to a solution of ethyl1-(1-phenylcyclopropyl)-1H-1,2,3-triazole-4-carboxylate (100 mg, 0.39mmol) in tetrahydrofuran (3 mL) and water (1 mL). The resulting solutionwas stirred overnight at room temperature, concentrated under vacuum anddiluted with water (5 mL). The pH of the solution was adjusted to 5 withaqueous hydrochloric acid (1 N, 5 mL). The resulting solution wasextracted with ethyl acetate (3×5 mL). The combined organic layers werewashed with brine, dried over anhydrous sodium sulfate, and filtered.The filtrate was concentrated under vacuum to afford the title compound(30 mg crude) as a white solid. LC-MS (Method D): m/z=230.2 [M+H]⁺,0.532 min.

Step 6: Preparation of(S)—N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1-(1-phenylcyclopropyl)-1H-1,2,3-triazole-4-carboxamide

The crude product obtained using Amide Coupling Procedure C was purifiedby Prep-HPLC with the following conditions: Column: XBridge Shield RP18OBD Column, 5 μm, 19×150 mm; Mobile Phase A: water (0.1% formic acid),Mobile Phase B: ACN; Flow rate: 20 mL/min; Gradient: 35% B to 65% B over7 min; 220 nm; Rt: 6 min to afford the title compound. ¹H NMR (300 MHz,DMSO-d₆) δ 8.88 (s, 1H), 8.58 (d, J=8.1 Hz, 1H), 7.53-7.49 (m, 1H),7.39-7.20 (m, 5H), 7.07-7.04 (m, 2H), 4.89-4.81 (m, 1H), 4.65-4.55 (m,1H), 4.43-4.30 (m, 1H), 3.32 (s, 3H), 1.79-1.78 (m, 2H), 1.73-1.64 (m,2H). LC-MS (Method D): m/z=404.1 [M+H]⁺, 1.992 min.

Example 88:(S)—N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-2-(1-phenylcyclopropyl)-1H-imidazole-5-carboxamide

Step 1: Preparation of(Z)—N′-hydroxy-1-phenylcyclopropanecarboximidamide

Hydroxylamine hydrochloride (1.4 g, 20.3 mmol) was added to a mixture of1-phenylcyclopropanecarbonitrile (1.5 g, 10.5 mmol) and sodium carbonate(2.2 g, 20.7 mmol) in ethanol (20 mL) and water (10 mL). The resultingmixture was stirred at 80° C. for 18 hours. After cooling to roomtemperature, the reaction mixture was diluted with water (50 mL) andextracted with dichloromethane (3×80 mL). The combined organic layerswere washed with brine, dried over anhydrous sodium sulfate, filteredand concentrated under vacuum. The residue was purified by columnchromatography (ethyl acetate/petroleum ether, 1/20) to afford the titlecompound (1.2 g, 68%) as a white solid. LC-MS (Method E): m/z=176.8[M+H]⁺, 0.371 min.

Step 2: Preparation of ethyl2-(1-phenylcyclopropyl)-1H-imidazole-5-carboxylate

A solution of (Z)—N′-hydroxy-1-phenylcyclopropanecarboximidamide (1.2 g,6.8 mmol) and ethyl propiolate (1.0 g, 10.2 mmol) in ethanol (50 mL) wasstirred at 80° C. overnight and concentrated under vacuum. The residuewas dissolved in oxydibenzene (20 mL) and the mixture was stirred at200° C. for 2 hours. The resulting mixture was concentrated and purifiedby column chromatography (ethyl acetate/petroleum ether, 1/5) to affordthe title compound (0.7 g, 40%) as a yellow solid. LC-MS (Method C):m/z=257.0 [M+H]⁺, 1.200 min.

Step 3: Preparation of 2-(1-phenylcyclopropyl)-1H-imidazole-5-carboxylicacid

Lithium hydroxide (288 mg, 7.2 mmol) was added to a solution of2-(1-phenylcyclopropyl)-1H-imidazole-5-carboxylate (300 mg, 1.2 mmol) intetrahydrofuran (9 mL) and water (3 mL). The reaction mixture wasstirred overnight at room temperature, diluted with water (20 mL),adjusted pH to 5 with aqueous hydrochloric acid (1 N, 10 mL) andextracted with ethyl acetate (3×20 mL). The combined organic layers werewashed with brine, dried over anhydrous sodium sulfate, and filtered.The filtrate was concentrated under vacuum to afford the title compound(130 mg crude) as a yellow solid. LC-MS (Method C): m/z=229.1 [M+H]⁺,0.906 min.

Step 4: Preparation of(S)—N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-2-(1-phenylcyclopropyl)-1H-imidazole-5-carboxamide

The crude product obtained using Amide Coupling Procedure C was purifiedby Prep-HPLC with the following conditions: Column: X Bridge Prep C18OBD Column, 5 μm, 19×150 mm; Mobile Phase A: water (10 mmol/L NH₄HCO₃),Mobile Phase B: ACN; Flow rate: 20 mL/min; Gradient: 35% B to 60% B over7 min; UV 254 & 220 nm to afford the title compound. ¹H NMR (300 MHz,DMSO-d₆) δ 12.28 (s, 1H), 7.86 (d, J=8.1 Hz, 1H), 7.52-7.49 (m, 2H),7.37-7.19 (m, 8H), 4.89-4.79 (m, 1H), 4.54-4.38 (m, 2H), 3.33 (s, 3H),1.48-1.40 (m, 2H), 1.28-1.20 (m, 2H). LC-MS (Method O): m/z=403.1[M+H]⁺, 1.389 min.

Example 89A:5-benzyl-N-((1aR,2R,8bS)-5,7-difluoro-3-oxo-1,1a,2,3,4,8b-hexahydrobenzo[b]cyclopropa[d]azepin-2-yl)-1,3,4-oxadiazole-2-carboxamide

Step 1: Preparation of ethyl2-oxo-2-(2-(2-phenylacetyl)hydrazinyl)acetate

Ethyl 2-chloro-2-oxoacetate (603 mg, 4.4 mmol) was added to a stirringsolution of 2-phenylacetohydrazide (660 mg, 4.4 mmol) and triethylamine(1.33 g, 13.2 mmol) in dichloromethane (20 mL). The reaction mixture wasstirred at room temperature for 5 hours, quenched by the addition ofwater (20 mL) and extracted with dichloromethane (3×25 mL). The combinedorganic layers were washed with brine, dried over anhydrous sodiumsulfate, filtered and concentrated under vacuum. The residue waspurified by column chromatography (ethyl acetate/petroleum ether, 1/3)to afford the title compound (550 mg, 50%) as a yellow oil. LC-MS(Method S): m/z=251.0 [M+H]⁺, 0.679 min.

Step 2: Preparation of ethyl 5-benzyl-1,3,4-oxadiazole-2-carboxylate

Tosyl chloride (840 mg, 4.4 mmol) was added to a stirring solution ofethyl 2-oxo-2-(2-(2-phenylacetyl)hydrazinyl)acetate (666 mg, 6.6 mmol)in tetrahydrofuran (25 mL). The reaction mixture was stirred overnightat room temperature, quenched by the addition of water (20 mL) andextracted with dichloromethane (3×25 mL). The combined organic layerswere washed with brine, dried over anhydrous sodium sulfate, filteredand concentrated under vacuum. The residue was purified by columnchromatography (ethyl acetate/petroleum ether, 1/3) to afford the titlecompound (500 mg, 98%) as a yellow oil. LC-MS (Method C): m/z=233.0[M+H]⁺, 1.200 min.

Step 3: Preparation of 5-benzyl-1,3,4-oxadiazole-2-carboxylic acid

Lithium hydroxide (103 mg, 4.3 mmol) was added to a stirring solution ofethyl 5-benzyl-1,3,4-oxadiazole-2-carboxylate (500 mg, 2.15 mmol) intetrahydrofuran (5 mL) and water (2 mL). The reaction mixture wasstirred overnight at room temperature, concentrated under vacuum anddiluted with water (20 mL). The pH value of the mixture was adjusted topH=6 with aqueous hydrochloric acid (1 N, 10 mL). The resulting solutionwas extracted with ethyl acetate (3×50 mL). The combined organic layerswere washed with brine, dried over anhydrous sodium sulfate, filteredand concentrated under vacuum to afford the title compound (250 mgcrude) as a yellow semi-solid. LC-MS (Method I): m/z=205.0 [M+H]⁺, 0.058min.

Step 4: Preparation of5-benzyl-N-((1aR,2R,8bS)-5,7-difluoro-3-oxo-1,1a,2,3,4,8b-hexahydrobenzo[b]cyclopropa[d]azepin-2-yl)-1,3,4-oxadiazole-2-carboxamide

The crude product obtained using Amide Coupling Procedure C was purifiedby Prep-HPLC with the following conditions: Column, XBridge C18 OBD PrepColumn, 5 μm, 19 mm×250 mm; mobile phase, water (10 mmol/L NH₄HCO₃) andACN (30.0% ACN up to 60.0% over 7 min); Detector, UV 254 nm to affordthe title compound. ¹H NMR (400 MHz, CD₃OD) δ 7.38-7.29 (m, 5H),7.12-7.08 (m, 1H), 6.98-6.93 (m, 1H), 4.82 (d, J=0.8 Hz, 1H), 4.36 (s,2H), 2.31-2.25 (m, 1H), 2.12-2.07 (m, 1H), 1.67-1.63 (m, 1H), 1.23-1.17(m, 1H). LC-MS (Method V): m/z=411.05 [M+H]⁺, 2.915 min.

Example 89B:5-benzyl-N-((1aS,2S,8bR)-5,7-difluoro-3-oxo-1,1a,2,3,4,8b-hexahydrobenzo[b]cyclopropa[d]azepin-2-yl)-1,3,4-oxadiazole-2-carboxamide

The crude product obtained using Amide Coupling Procedure C was purifiedby Prep-HPLC with the following conditions: Column, XBridge C18 OBD PrepColumn, 5 μm, 19 mm×250 mm; mobile phase, water (10 mmol/L NH₄HCO₃) andACN (30.0% ACN to 60.0% over 7 min); Detector, UV 254 nm to afford thetitle compound. ¹H NMR (400 MHz, CD₃OD) δ 7.39-7.28 (m, 5H), 7.11-7.08(m, 1H), 6.98-6.93 (m, 1H), 4.81 (d, J=0.8 Hz, 1H), 4.36 (s, 2H),2.31-2.25 (m, 1H), 2.12-2.07 (m, 1H), 1.67-1.63 (m, 1H), 1.23-1.17 (m,1H). LC-MS (Method Q): m/z=411.30 [M+H]⁺, 0.965 min.

Example 90A:1-benzyl-N-((1aR,2R,8bS)-5,7-difluoro-3-oxo-1,1a,2,3,4,8b-hexahydrobenzo[b]cyclopropa[d]azepin-2-yl)-1H-1,2,3-triazole-4-carboxamide

The crude product obtained using Amide Coupling Procedure C was purifiedby Prep-HPLC with the following conditions: Column, XBridge C18 OBD PrepColumn, 5 μm, 19 mm×250 mm; mobile phase, water (10 mmol/L NH₄HCO₃) andACN (30.0% ACN up to 60.0% over 7 min); Detector, UV 254 nm to affordthe title compound. ¹H NMR (400 MHz, DMSO-d₆) δ 9.90 (br. s, 1H), 8.77(s, 1H), 8.51 (d, J=7.0 Hz, 1H), 7.43-7.33 (m, 5H), 7.32-7.26 (m, 1H),7.24-7.19 (m, 1H), 5.67 (s, 2H), 4.63 (d, J=6.9 Hz, 1H), 2.32-2.26 (m,1H), 2.06-2.00 (m, 1H), 1.44-1.40 (m, 1H), 1.14-1.08 (m, 1H). LC-MS(Method D): m/z=410.10 [M+H]⁺, 1.876 min.

Example 90B:1-benzyl-N-((1aS,2S,8bR)-5,7-difluoro-3-oxo-1,1a,2,3,4,8b-hexahydrobenzo[b]cyclopropa[d]azepin-2-yl)-1H-1,2,3-triazole-4-carboxamide

The crude product obtained using Amide Coupling Procedure C was purifiedby Prep-HPLC with the following conditions: Column, XBridge C18 OBD PrepColumn, 5 μm, 19 mm×250 mm; mobile phase, water (10 mmol/L NH₄HCO₃) andACN (30.0% ACN to 60.0% over 7 min); Detector, UV 254 nm to afford thetitle compound. ¹H NMR (400 MHz, DMSO-d₆) δ 9.90 (s, 1H), 8.77 (s, 1H),8.51 (d, J=7.0 Hz, 1H), 7.46-7.33 (m, 5H), 7.30-7.26 (m, 1H), 7.24-7.19(m, 1H), 5.67 (s, 2H), 4.63 (d, J=6.9 Hz, 1H), 2.32-2.26 (m, 1H),2.05-2.00 (m, 1H), 1.45-1.40 (m, 1H), 1.14-1.08 (m, 1H). LC-MS (MethodJ): m/z=410.15 [M+H]⁺, 1.269 min.

Example 91:(S)—N-(4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepin-3-yl)-5-(1-phenylcyclopropyl)-1H-pyrazole-3-carboxamide

The crude product obtained using Amide Coupling Procedure C was purifiedby Prep-HPLC with the following conditions: Column: X Bridge Prep PhenylOBD Column, 5 μm, 19×150 mm; Mobile Phase A: water (0.1% formic acid),Mobile Phase B: ACN; Flow rate: 20 mL/min; Gradient: 25% B to 60% B over7 min; UV 254 &220 nm to afford the title compound. ¹H NMR (400 MHz,DMSO-d₆) δ 13.18 (s, 1H), 10.53 (s, 1H), 8.24-8.14 (m, 2H), 7.56 (dd,J=8.0, 1.6 Hz, 1H), 7.34-7.15 (m, 6H), 6.38 (s, 1H), 4.84-4.77 (m, 1H),4.52-4.41 (m, 2H), 1.35-1.30 (m, 4H). LC-MS (Method D): m/z=390.1[M+H]⁺, 1.537 min.

Example92:1-benzyl-N-((2R,3S)-2,5-dimethyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepin-3-yl)-4-fluoro-1H-pyrazole-3-carboxamide

Step 1: Preparation of(2S,3R)-2-(tert-butoxycarbonylamino)-3-(2-nitropyridin-3-yloxy)-butanoicacid

Sodium hydride (60%, 9.2 g, 230 mmol) was added to a stirring solutionof (2S,3R)-2-(tert-butoxycarbonylamino)-3-hydroxybutanoic acid (25 g,115 mmol) in N,N-dimethylformamide (500 mL) and the reaction mixture wasstirred at 0° C. for 1 hour. After addition of 3-fluoro-2-nitropyridine(16.4 g, 115 mmol), the reaction mixture was stirred at room temperaturefor another 2 hours and then quenched by the addition of hydrochlorideacid (3 N, 20 mL). The pH value of the reaction solution was adjusted to3-4 with hydrogen chloride (3 N, 20 mL). The resulting solution wasextracted with ethyl acetate (3×150 mL). The organic layers werecombined, dried over anhydrous sodium sulfate and concentrated underreduced pressure. The residue was purified by reverse phase columnchromatography (acetonitrile/water, 1/2) to afford the title compound(3.8 g, 10%) as a light yellow oil. LC-MS (Method C): m/z=286.1[M+H-56]⁺, 1.167 min.

Step 2: Preparation of(2S,3R)-3-(2-aminopyridin-3-yloxy)-2-(tert-butoxycarbonylamino)-butanoicacid

(2S,3R)-2-(tert-butoxycarbonylamino)-3-(2-nitropyridin-3-yloxy)butanoicacid (3.77 g, 11 mmol) in methanol (30 mL) was hydrogenated in thepresence of palladium carbon (10%, 1.0 g) under a hydrogen atmosphere(2-3 atm). The reaction mixture was stirred for 6 hours at roomtemperature. The solids were removed by filtration and the filtrate wasconcentrated under vacuum to afford the title compound (3.12 g, 91%) asa colorless oil. LC-MS (Method C): m/z=312.1 [M+H]⁺, 0.887 min.

Step 3: Preparation of tert-butyl(2R,3S)-2-methyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepin-3-ylcarbamate

N,N-diisopropylethylamine (1.43 g, 11 mmol) was added to a stirringsolution of(2S,3R)-3-(2-aminopyridin-3-yloxy)-2-(tert-butoxycarbonylamino)butanoicacid (3.0 g, 10 mmol) andN,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uroniumhexafluorophospate (4.18 g, 11 mmol) in N,N-dimethylformamide (50 mL).The reaction mixture was stirred for 5 hours at room temperature,quenched by the addition of water (20 mL) and extracted with ethylacetate (3×100 mL). The combined organic layers were washed with brine,dried over anhydrous sodium sulfate and concentrated under vacuum. Theresidue was purified by column chromatography (methanol/dichloromethane,1/20) to afford the title compound (2.2 g, 78%) as a white solid. LC-MS(Method C): m/z=294.1 [M+H]⁺, 1.136 min.

Step 4: Preparation of tert-butyl(2R,3S)-2,5-dimethyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepin-3-ylcarbamate

Iodomethane (388 mg, 2.73 mmol) was added dropwise to a stirringsolution of tert-butyl(2R,3S)-2-methyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepin-3-ylcarbamate(800 mg, 2.73 mmol) and cesium carbonate (890 mg, 2.73 mmol) inN,N-dimethylformamide (15 mL). The reaction mixture was stirred for 1hour at 0° C. and 3 hours at room temperature, diluted with water (20mL) and extracted with ethyl acetate (3×100 mL). The combined organiclayers were washed with brine, dried over anhydrous sodium sulfate,filtered and concentrated under vacuum. The residue was purified bycolumn chromatography (methanol/dichloromethane, 1/10) to afford thetitle compound (670 mg, 80%) as a white solid. LC-MS (Method C):m/z=308.2 [M+H]⁺, 1.250 min.

Step 5: Preparation of(2R,3S)-3-amino-2,5-dimethyl-2,3-dihydropyrido[3,2-b][1,4]oxazepin-4(5H)-onehydrochloride

Tert-butyl(2R,3S)-2,5-dimethyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepin-3-ylcarbamate(670 mg, 2.18 mmol) was added to a solution of hydrogen chloride indioxane (4 M, 10 mL, 40 mmol). The reaction mixture was stirred for 5hours at room temperature and concentrated under reduced pressure toafford the title compound (460 mg crude) as a white solid. LC-MS (MethodE): m/z=207.90 [M+H]⁺, 0.432 min.

Step 6: Preparation of1-benzyl-N-((2R,3S)-2,5-dimethyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepin-3-yl)-4-fluoro-1H-pyrazole-3-carboxamide

The crude product obtained using Amide Coupling Procedure C was purifiedby Prep-HPLC with the following conditions: Column: X Bridge C18 OBDPrep Column, 5 μm, 19 mm×250 mm; Mobile Phase A: water (10 mmol/LNH₄HCO₃), Mobile Phase B: ACN; Flow rate: 20 mL/min; Gradient: 40% B to60% B in 7 min; UV 254 & 220 nm to afford the title compound. ¹H NMR(400 MHz, DMSO-d₆) δ 8.36 (dd, J=4.4, 1.6 Hz, 1H), 8.15 (d, J=4.4 Hz,1H), 7.76 (dd, J=8.0, 1.6 Hz, 1H), 7.61 (d, J=6.4 Hz, 1H), 7.42-7.31 (m,4H), 7.31-7.27 (m, 2H), 5.37 (s, 2H), 5.00-4.93 (m, 1H), 4.92-4.88 (m,1H), 3.40 (s, 3H), 1.32 (d, J=6.0 Hz, 3H). LC-MS (Method F): m/z=409.9[M+H]⁺, 1.336 min.

Example93:1-benzyl-N-((2S,3S)-2,5-dimethyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepin-3-yl)-4-fluoro-1H-pyrazole-3-carboxamide

The title compound was prepared from(2S,3S)-2-(tert-butoxycarbonylamino)-3-hydroxybutanoic acid using theprocedure described in Example 92.

The crude product obtained was purified by Prep-HPLC with the followingconditions: Column: X Bridge Prep C18 OBD Column 19×150 mm, 5 μm; MobilePhase A: water (10 mmol/L NH₄HCO₃), Mobile Phase B: ACN; Flow rate: 20mL/min; Gradient: 25% B to 55% B over 7 min; UV 254 & 220 nm to affordthe title compound. ¹H NMR (400 MHz, DMSO-d₆) δ 8.46 (d, J=8.4 Hz, 1H),8.38 (dd, J=4.8, 1.2 Hz, 1H), 8.14 (d, J=4.4 Hz, 1H), 7.63 (dd, J=8.0,1.6 Hz, 1H), 7.42-7.27 (m, 6H), 5.36 (s, 2H), 5.10-5.01 (m, 1H),4.45-4.40 (m, 1H), 3.34 (s, 3H), 1.26 (d, J=6.0 Hz, 3H). LC-MS (MethodD): m/z=410.1 [M+H]⁺, 1.923 min.

Example 94:5-benzyl-N-((2R,3S)-2,5-dimethyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepin-3-yl)-4H-1,2,4-triazole-3-carboxamide

N,N-diisopropylethylamine (95 mg, 0.73 mmol) was added to a mixture of5-benzyl-4H-1,2,4-triazole-3-carboxylic acid (50 mg, 0.24 mmol),(2R,3S)-3-amino-2,5-dimethyl-2,3-dihydropyrido[3,2-b][1,4]oxazepin-4(5H)-onehydrochloride (50 mg, 0.24 mmol),N-(3-dimethylaminopropyl))-N′-ethylcarbodiimide hydrochloride (60 mg,0.32 mmol) and 1-hydroxybenzotriazole (43 mg, 0.32 mmol) inN,N-dimethylformamide (2 mL). The reaction mixture was stirred overnightat room temperature, diluted with water (20 mL) and extracted with ethylacetate (3×50 mL). The organic layers were combined, washed with brine,dried over anhydrous sodium sulfate, filtered and concentrated undervacuum. The crude product obtained using Amide Coupling Procedure C waspurified by Prep-HPLC with the following conditions: Column: X BridgeShield RP18 OBD Column, 5 μm, 19×150 mm; Mobile Phase A: water (0.05%TFA), Mobile Phase B: ACN; Flow rate: 20 mL/min; Gradient: 5% B to 5% Bover 4 min; UV 254 & 220 nm to afford the title compound. ¹H NMR (400MHz, DMSO-d₆) δ 14.46 (s, 1H), 8.36 (dd, J=4.8, 1.6 Hz, 1H), 7.98 (d,J=6.0 Hz, 1H), 7.76 (dd, J=8.0, 1.6 Hz, 1H), 7.38-7.23 (m, 6H),5.01-4.94 (m, 1H), 4.93-4.89 (m, 1H), 4.14 (s, 2H), 3.40 (s, 3H), 1.31(d, J=6.0 Hz, 3H). LC-MS (Method D): m/z=393.1 [M+H]⁺, 1.725 min.

Example 95:5-benzyl-N-((2S,3S)-2,5-dimethyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepin-3-yl)-4H-1,2,4-triazole-3-carboxamide

Example 96:5-benzyl-N-((2R,3S)-2-methyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepin-3-yl)-4H-1,2,4-triazole-3-carboxamide

Step 1: Preparation of(2R,3S)-3-amino-2-methyl-2,3-dihydropyrido[3,2-b][1,4]oxazepin-4(5H)-onehydrochloride

Tert-butyl(2R,3S)-2-methyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepin-3-ylcarbamate(100 mg, 0.34 mmol) was added to a solution of hydrogen chloride indioxane (4 M, 5 mL). The reaction mixture was stirred for 2 hours atroom temperature and concentrated under reduced pressure to afford thetitle compound (100 mg crude) as a white solid. LC-MS (Method E):m/z=194.0 [M+H]⁺, 0.432 min.

Step 2: Preparation of5-benzyl-N-((2R,3S)-2-methyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepin-3-yl)-4H-1,2,4-triazole-3-carboxamide

The crude product obtained using Amide Coupling Procedure C was purifiedby Prep-HPLC with the following conditions: Column: X Bridge C18 OBDPrep Column, 10 μm, 19 mm×250 mm; Mobile Phase A: water (0.1% formicacid), Mobile Phase B: ACN; Flow rate: 20 mL/min; Gradient: 20% B to 35%B over 7 min UV 254 & 220 nm to afford the title compound. ¹H NMR (300MHz, DMSO-d₆) δ 14.41 (s, 1H), 10.84 (s, 1H), 8.19-8.08 (m, 2H), 7.62(dd, J=8.1, 1.2 Hz, 1H), 7.37-7.20 (m, 6H), 4.98-4.86 (m, 2H), 4.15 (s,2H), 1.30 (d, J=6.0 Hz, 3H). LC-MS (Method D): m/z=379.1 [M+H]⁺, 1.546min.

Example 97:5-benzyl-N-((2S,3S)-2-methyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepin-3-yl)-4H-1,2,4-triazole-3-carboxamide

Step 1: Preparation of(2S,3S)-3-amino-2-methyl-2,3-dihydropyrido[3,2-b][1,4]oxazepin-4(5H)-onehydrochloride

Tert-butyl(2S,3S)-2-methyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepin-3-ylcarbamate (50 mg, 0.17 mmol) was added to a solution of hydrogenchloride in dioxane (4 M, 5 mL, 20 mmol). The reaction mixture wasstirred for 2 hours at room temperature and concentrated under vacuum toafford the title compound (35 mg crude) as a white solid. LC-MS (MethodE): m/z=194.0 [M+H]⁺, 0.432 min.

Step 2: Preparation of5-benzyl-N-((2S,3S)-2-methyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepin-3-yl)-4H-1,2,4-triazole-3-carboxamide

The crude product obtained using Amide Coupling Procedure C was purifiedby Prep-HPLC with the following conditions: Column: X Select CSH prepC18 OBD Prep Column, 5 μm, 19 mm×150 mm; Mobile Phase A: water (0.1%formic acid), Mobile Phase B: ACN; Flow rate: 20 mL/min; Gradient: 15% Bto 60% B over 7 min; UV 254 & 220 nm to afford the title compound. ¹HNMR (400 MHz, DMSO-d₆) δ 14.36 (s, 1H), 10.56 (s, 1H), 8.68 (d, J=8.8Hz, 1H), 8.23-8.20 (m, 1H), 7.56 (d, J=8.8 Hz, 1H), 7.39-7.17 (m, 6H),5.11-4.90 (m, 1H), 4.44 (m, 1H), 4.16 (s, 2H), 1.32 (d, J=6.0 Hz, 3H).LC-MS (Method F): m/z=378.95 [M+H]⁺, 0.932 min.

Example 98A and 98B:(R)-5-benzyl-N-(8′-oxo-6′,7′,8′,9′-tetrahydrospiro[cyclopropane-1,5′-pyrido[2,3-b]azepin]-7′-yl)-4H-1,2,4-triazole-3-carboxamide(98A) and(S)-5-benzyl-N-(8′-oxo-6′,7′,8′,9′-tetrahydrospiro[cyclopropane-1,5′-pyrido[2,3-b]azepin]-7′-yl)-4H-1,2,4-triazole-3-carboxamide(98B)

Step 1: Preparation of7′-amino-6′,7′-dihydrospiro[cyclopropane-1,5′-pyrido[2,3-b]azepin]-8′(9′H)-onehydrochloride

A solution of hydrogen chloride in 1,4-dioxane (4 N, 10 mL, 40 mmol) wasadded to a solution of tert-butyl(8′-oxo-6′,7′,8′,9′-tetrahydrospiro[cyclopropane-1,5′-pyrido[2,3-b]azepin]-7′-yl)carbamate(100 mg, 0.34 mmol) in 1,4-dioxane (4 mL). The reaction mixture wasstirred for 2 hours at room temperature and concentrated under highvacuum to afford the title compound (80 mg crude) as a white solid.LC-MS (Method C): m/z=204.1 [M+H]⁺, 0.677 min.

Step 2: Preparation of5-benzyl-N-(8′-oxo-6′,7′,8′,9′-tetrahydrospiro[cyclopropane-1,5′-pyrido[2,3-b]azepin]-7′-yl)-4H-1,2,4-triazole-3-carboxamide

The crude product obtained using Amide Coupling Procedure C was purifiedby Prep-HPLC with the following conditions: Column: XBridge Prep C18 OBDColumn, 5 μm, 19×150 mm; Mobile Phase A: waters (0.05% TFA), MobilePhase B: ACN; Flow rate: 20 mL/min; Gradient: 35% B to 65% B over 7 min;254/220 nm to afford the title compound (50 mg, 56%) as a white solid.LC-MS (Method V): m/z=389.2 [M+H]⁺, 0.982 min.

Step 2: Preparation of(R)-5-benzyl-N-(8′-oxo-6′,7′,8′,9′-tetrahydrospiro[cyclopropane-1,5′-pyrido[2,3-b]azepin]-7′-yl)-4H-1,2,4-triazole-3-carboxamide(First Eluting Isomer) and(S)-5-benzyl-N-(8′-oxo-6′,7′,8′,9′-tetrahydrospiro[cyclopropane-1,5′-pyrido[2,3-b]azepin]-7′-yl)-4H-1,2,4-triazole-3-carboxamide(Second Eluting Isomer)

The racemate of5-benzyl-N-(8′-oxo-6′,7′,8′,9′-tetrahydrospiro[cyclopropane-1,5′-pyrido[2,3-b]azepin]-7′-yl)-4H-1,2,4-triazole-3-carboxamide(50 mg, 0.128 mmol) was separated by Prep-Chiral-HPLC with the followingconditions: Column: Chiralpak ID-2, 2×25 cm, 5 μm; Mobile Phase A:hexane/DCM 4.5:1, Mobile Phase B: EtOH; Flow rate: 17 mL/min; Gradient:50% B to 50% B over 22 min; UV 254 & 220 nm; RT 1: 11.72 min; RT 2:18.02 min to afford the title compounds:

Example 98A (first eluting isomer): ¹H NMR (300 MHz, DMSO-d₆) δ 14.28(s, 1H), 10.37 (s, 1H), 8.27 (dd, J=4.8, 1.8 Hz, 1H), 7.69 (dd, J=7.6,1.8 Hz, 1H), 7.34-7.08 (m, 6H), 4.42-4.33 (m, 1H), 3.30 (s, 3H),2.82-2.68 (m, 1H), 1.72 (s, 1H), 1.23-1.05 (m, 1H), 0.88-0.78 (m, 1H),0.70-0.65 (m, 1H), 0.40-0.25 (m, 1H). LC-MS (Method D): m/z=389.2[M+H]⁺, 1.499 min.

Example 98B (second eluting isomer): ¹H NMR (300 MHz, DMSO-d₆) δ 10.38(d, J=2.8 Hz, 1H), 8.37-8.22 (m, 2H), 7.71-7.67 (m, 1H), 7.44-7.08 (m,6H), 4.43-4.34 (m, 1H), 4.06 (s, 2H), 2.78-2.71 (m, 1H), 1.73 (t, J=12.3Hz, 1H), 1.23-1.05 (m, 2H), 0.86-0.79 (m, 1H), 0.71-0.64 (m, 1H), 0.27(s, 1H). LC-MS (Method D): m/z=389.2 [M+H]⁺, 1.503 min.

Example 99:(S)—N-(5-methyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepin-3-yl)-5-(1-phenylcyclopropyl)-1H-imidazole-2-carboxamide

The crude product obtained using Amide Coupling Procedure C was purifiedby Prep-HPLC with the following conditions: column: X bridge Prep C18,19×150 mm, 5 μm; Mobile phase: Phase A: water (10 mmol/L NH₄HCO₃); PhaseB: ACN; Flow rate: 20 mL/min; Gradient: 25% B to 55% B over 7 min;Detector, UV 220 & 254 nm; Rt: 6.32 min to afford the title compound. ¹HNMR (300 MHz, DMSO-d₆) δ 12.80 (s, 1H), 8.50-8.32 (m, 2H), 7.72-7.70 (m,1H), 7.39-7.15 (m, 6H), 6.78-6.65 (m, 1H), 4.92-4.63 (m, 2H), 4.52-4.48(m, 1H), 3.36 (s, 3H), 1.35-1.30 (m, 2H), 1.28-1.11 (m, 2H). LC-MS(Method O): m/z=404.0 [M+H]⁺, 1.412 min.

Example 100A and 100B:4-(2-fluorophenoxy)-N-((1aS,2S,8bR)-4-methyl-3-oxo-1,1a,2,3,4,8b-hexahydrocyclopropa[d]pyrido[2,3-b]azepin-2-yl)picolinamide(100A) and4-(2-fluorophenoxy)-N-((1aR,2R,8bS)-4-methyl-3-oxo-1,1a,2,3,4,8b-hexahydrocyclopropa[d]pyrido[2,3-b]azepin-2-yl)picolinamide(100B)

Step 1: Preparation of4-(2-fluorophenoxy)-N-(cis-4-methyl-3-oxo-1,1a,2,3,4,8b-hexahydrocyclopropa[d]pyrido[2,3-b]azepin-2-yl)picolinamide

The crude product obtained using Amide Coupling Procedure C was purifiedby prep-TLC (ethyl acetate/petroleum ether, 1/3) to afford the titleracemic compound. LC-MS (Method J): m/z=419.1 [M+H]⁺, 1.330 min.

Step 2: Preparation of4-(2-fluorophenoxy)-N-((1aS,2S,8bR)-4-methyl-3-oxo-1,1a,2,3,4,8b-hexahydrocyclopropa[d]pyrido[2,3-b]azepin-2-yl)picolinamide(First Eluting Isomer) and4-(2-fluorophenoxy)-N-((1aR,2R,8bS)-4-methyl-3-oxo-1,1a,2,3,4,8b-hexahydrocyclopropa[d]pyrido[2,3-b]azepin-2-yl)picolinamide(Second Eluting Isomer)

The racemate of4-(2-fluorophenoxy)-N-(cis-4-methyl-3-oxo-1,1a,2,3,4,8b-hexahydrocyclopropa[d]pyrido[2,3-b]azepin-2-yl)picolinamide (25 mg, 0.096 mmol)was separated by Prep-Chiral-HPLC with the following conditions: Column:Chiralpak IA, 2×25 cm, 5 μm; Mobile Phase A: hexane, Mobile Phase B:EtOH; Flow rate: 16 mL/min; Gradient: 50% B to 50% B over 19 min;220/254 nm; RT1: 13.609 min; RT2: 15.738 min to afford the titlecompounds:

Example 100A (first eluting isomer): ¹H NMR (300 MHz, Methanol-d₄) δ8.59 (d, J=5.6 Hz, 1H), 8.39 (dd, J=4.7, 1.8 Hz, 1H), 7.95 (dd, J=7.7,1.8 Hz, 1H), 7.55 (d, J=2.5 Hz, 1H), 7.42-7.27 (m, 5H), 7.15 (dd, J=5.6,2.6 Hz, 1H), 4.66 (s, 1H), 3.42 (s, 3H), 2.32-2.26 (m, 1H), 2.17-2.06(m, 1H), 1.36-1.32 (m, 1H), 1.23-1.14 (m, 1H). LC-MS (Method J):m/z=419.2 [M+H]⁺, 1.467 min.

Example 100B (second eluting isomer): ¹H NMR (300 MHz, Methanol-d₄) δ8.58 (d, J=5.6 Hz, 1H), 8.38 (dd, J=4.7, 1.8 Hz, 1H), 7.95 (dd, J=7.7,1.8 Hz, 1H), 7.55 (d, J=2.6 Hz, 1H), 7.41-7.28 (m, 5H), 7.14 (dd, J=5.6,2.6 Hz, 1H), 4.65 (s, 1H), 3.42 (s, 3H), 2.35-2.25 (m, 1H), 2.15-2.03(m, 1H), 1.37-1.25 (m, 1H), 1.24-1.16 (m, 1H). LC-MS (Method T):m/z=419.3 [M+H]⁺, 2.774 min.

Example 101A and 101B:(R)-5-benzyl-N-(1,4-dimethyl-5-oxo-1,4,5,6,7,8-hexahydropyrazolo[4,3-b]azepin-6-yl)-4H-1,2,4-triazole-3-carboxamide(101A) and(S)-5-benzyl-N-(1,4-dimethyl-5-oxo-1,4,5,6,7,8-hexahydropyrazolo[4,3-b]azepin-6-yl)-4H-1,2,4-triazole-3-carboxamide(101B)

Step 1: Preparation of ethyl4-(1-methyl-4-nitro-1H-pyrazol-5-yl)butanoate

To a stirring solution of 5-bromo-1-methyl-4-nitro-1H-pyrazole (2.0 g,9.76 mmol), (4-ethoxy-4-oxobutyl)zinc(II) bromide (0.5 M intetrahydrofuran) (29.2 mL, 14.6 mmol) anddicyclohexyl(2′,6′-dimethoxybiphenyl-2-yl)phosphine (402.3 mg, 0.98mmol) in tetrahydrofuran (100 mL) was added a solution of palladiumdiacetate (109.8 mg, 0.49 mmol) in tetrahydrofuran dropwise withstirring under a nitrogen atmosphere. The resulting mixture was heatedovernight at 40° C. The reaction mixture was concentrated under highvacuum and the residue was purified by column chromatography(methanol/dichloromethane, 1/99) to afford the title compound (445 mg,18.9%) as a yellow oil. LC-MS (Method C): m/z=242.1 [M+H]⁺, 1.156 min.

Step 2: Preparation of ethyl4-(4-amino-1-methyl-1H-pyrazol-5-yl)butanoate

Ethyl 4-(1-methyl-4-nitro-1H-pyrazol-5-yl)butanoate (405 mg, 1.68 mmol)was hydrogenated in the presence of palladium on carbon (10%, 41 mg)under a hydrogen atmosphere (2-3 atm) in methanol (20 mL). The reactionmixture was stirred for 2 hours at room temperature. Then the solidswere removed by filtration and the solvents were evaporated under vacuumto afford the title compound (320 mg crude) as a yellow solid. LC-MS(Method C): m/z=212.2 [M+H]⁺, 0.768 min.

Step 3: Preparation of 4-(4-amino-1-methyl-1H-pyrazol-5-yl)butanoic acid

A solution of ethyl 4-(4-amino-1-methyl-1H-pyrazol-5-yl)butanoate (320mg, 1.51 mmol) and lithium hydroxide (108.9 mg, 4.53 mmol) intetrahydrofuran/water=3/1 (4 mL) was stirred for 3 hours at roomtemperature. The pH value of the solution was adjusted to 6-7 withhydrochloride acid (1 N). The resulting solution was concentrated undervacuum to afford the title compound (220 mg crude) as a yellow solid.LC-MS (Method C): m/z=184.1 [M+H]⁺, 0.318 min.

Step 4: Preparation of1-methyl-7,8-dihydropyrazolo[4,3-b]azepin-5(1H,4H,6H)-one

N,N-diisopropylethylamine (465.2 mg, 3.6 mmol) was added to a stirringsolution of 4-(4-amino-1-methyl-1H-pyrazol-5-yl)butanoic acid (220 mg,1.2 mmol) and N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uroniumhexafluorophospate (548.2 mg, 1.44 mmol) in N,N-dimethylformamide (5mL). The reaction mixture was stirred for 2 hours at room temperature,diluted with water (10 mL) and extracted with ethyl acetate (3×20 mL).The combined organic layers were washed with brine, dried over anhydroussodium sulfate, filtered and concentrated under vacuum. The residue waspurified by column chromatography (ethyl acetate/petroleum ether, 1/4)to afford the title compound (160 mg, 80.8%) as a yellow solid. LC-MS(Method C): m/z=166.2 [M+H]⁺, 0.751 min.

Step 5: Preparation of1,4-dimethyl-7,8-dihydropyrazolo[4,3-b]azepin-5(1H,4H,6H)-one

Iodomethane (150.5 mg, 1.06 mmol) was added dropwise to a stirredsolution of 1-methyl-7,8-dihydropyrazolo[4,3-b]azepin-5(1H,4H,6H)-one(160 mg, 0.96 mmol) and sodium hydride (60%) (42.4 mg, 1.06 mmol) inN,N-dimethylformamide (5 mL) with stirring. The reaction mixture wasstirred for 2 hours at room temperature, quenched by water (10 mL) andextracted with ethyl acetate (3×20 mL). The combined organic phases weredried over anhydrous sodium sulfate, filtered and concentrated undervacuum. The residue was purified by column chromatography (petroleumether/ethyl acetate, 3/1) to afford the title compound (140 mg, 81.5%)as a yellow solid. LC-MS (Method C): m/z=180.2 [M+H]⁺, 0.816 min.

Step 6: Preparation of6-iodo-1,4-dimethyl-7,8-dihydropyrazolo[4,3-b]azepin-5(1H,4H,6H)-one

N¹,N¹,N²,N²-tetramethylethane-1,2-diamine (271.4 mg, 2.34 mmol) wasadded to a stirring solution of1,4-dimethyl-7,8-dihydropyrazolo[4,3-b]azepin-5(1H,4H,6H)-one (140 mg,0.78 mmol) in dichloromethane (5 mL) at 0° C. followed by the additionof iodotrimethylsilane (468 mg, 2.34 mmol). The reaction mixture wasstirred for 1 hour at 0° C. After adding iodine (137.2 mg, 0.54 mmol),the reaction mixture was stirred for another 1 hour at 0° C. andquenched with aqueous sodium thiosulfate (5%, 15 mL). The reactionmixture was stirred for another 15 minutes and extracted with ethylacetate (3×20 mL). The combined organic layers were washed with brine,dried over anhydrous sodium sulfate, filtered and concentrated undervacuum to afford the title compound (214 mg crude) as a yellow solid,which was used directly in the next step without further purification.LC-MS (Method C): m/z=306.0 [M+H]⁺, 0.953 min.

Step 7: Preparation of6-amino-,4-dimethyl-7,8-dihydropyrazolo[4,3-b]azepin-5(1H,4H,6H)-one

To a solution of6-iodo-1,4-dimethyl-7,8-dihydropyrazolo[4,3-b]azepin-5(1H,4H,6H)-one(214 mg, 0.70 mmol) in N,N-dimethylformamide (4 mL) was added sodiumazide (136.9 mg, 2.1 mmol). The reaction mixture was stirred for 2 hoursat room temperature and concentrated under reduced pressure. The residuewas dissolved in tetrahydrofuran (6 mL) and water (2 mL) andtriphenylphosphine (551.8 mg, 2.1 mmol) was added in one portion. Thereaction mixture was stirred at 50° C. overnight, diluted with water (10mL) and extracted with ethyl acetate (3×20 mL). The combined organiclayers were washed with brine, dried over anhydrous sodium sulfate,filtered and concentrated under vacuum. The residue was purified bycolumn chromatography (methanol/dichloromethane, 1/10) to afford thetitle compound (100 mg, 73.6%) as a yellow solid. LC-MS (Method C):m/z=195.1 [M+H]⁺, 0.386 min.

Step 8: Preparation of5-benzyl-N-(1,4-dimethyl-5-oxo-1,4,5,6,7,8-hexahydropyrazolo[4,3-b]azepin-6-yl)-4H-1,2,4-triazole-3-carboxamide

The crude product obtained using Amide Coupling Procedure C was purifiedby Prep-HPLC with the following conditions: column: X bridge Prep C18,19×150 mm, 5 μm; Mobile phase: Phase A: water (10 mmol/L NH₄HCO₃); PhaseB: ACN (20% to 80% over 12 min); Detector, UV 220 & 254 nm to afford thetitle compound. LC-MS (Method C): m/z=380.2 [M+H]⁺, 1.290 min.

Step 9: Preparation of(R)-5-benzyl-N-(1,4-dimethyl-5-oxo-1,4,5,6,7,8-hexahydropyrazolo[4,3-b]azepin-6-yl)-4H-1,2,4-triazole-3-carboxamide(First Eluting Isomer) and(S)-5-benzyl-N-(1,4-dimethyl-5-oxo-1,4,5,6,7,8-hexahydropyrazolo[4,3-b]azepin-6-yl)-4H-1,2,4-triazole-3-carboxamide(Second Eluting Isomer)

The racemate of5-benzyl-N-(1,4-dimethyl-5-oxo-1,4,5,6,7,8-hexahydropyrazolo[4,3-b]azepin-6-yl)-4H-1,2,4-triazole-3-carboxamide(50 mg, 0.13 mmol) were separated by Prep-Chiral-HPLC with the followingconditions: Column: Chiralpak IA, 2×25 cm, 5 μm; Mobile Phase A: Hex,Mobile Phase B: EtOH; Flow rate: 15 mL/min; Gradient: 60% B to 60% Bover 21 min; 220/254 nm; RT1: 12.12 min; RT2: 18.44 min.

Example 101A (first eluting isomer): ¹H NMR (400 MHz, Methanol-d₄) δ7.51 (s, 1H), 7.34-7.22 (m, 5H), 4.60 (dd, J=2.0, 10.0 Hz, 1H), 4.17 (s,2H), 3.80 (s, 3H), 3.36 (s, 3H), 3.20-3.11 (m, 1H), 2.99-2.91 (m, 1H),2.48-2.41 (m, 1H), 2.25-2.14 (m, 1H). LC-MS (Method V): m/z=380.1[M+H]⁺, 2.240 min.

Example 101B (second eluting isomer): ¹H NMR (400 MHz, Methanol-d₄) δ7.51 (s, 1H), 7.35-7.22 (m, 5H), 4.60 (dd, J=2.4, 10.4 Hz, 1H), 4.17 (s,2H), 3.80 (s, 3H), 3.36 (s, 3H), 3.20-3.11 (m, 1H), 2.99-2.91 (m, 1H),2.49-2.41 (m, 1H), 2.25-2.14 (m, 1H). LC-MS (Method D): m/z=380.2[M+H]⁺, 1.471 min.

Example 102A & 102B:5-((R)-2,3-dihydro-1H-inden-1-yl)-N—((S)-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepin-3-yl)-4H-1,2,4-triazole-3-carboxamideand5-((S)-2,3-dihydro-1H-inden-1-yl)-N—((S)-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepin-3-yl)-4H-1,2,4-triazole-3-carboxamide

Step 1: Preparation of5-(2,3-dihydro-1H-inden-1-yl)-N—((S)-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepin-3-yl)-4H-1,2,4-triazole-3-carboxamide

The crude product obtained using the procedure described in Example 54was purified by Prep-HPLC with the following conditions: Column: XBridgeC18 OBD Prep Column, 5 μm, 19 mm×250 mm; Mobile Phase A: water (10mmol/L NH₄HCO₃), Mobile Phase B: ACN; Flow rate: 20 mL/min; Gradient:20% B to 36% B over 7 min; 254 nm; Rt: 7 min to afford the titlecompound. LC-MS (Method D): m/z=391.1 [M+H]⁺, 1.593 min.

Step 2: Preparation of5-((R)-2,3-dihydro-1H-inden-1-yl)-N—((S)-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepin-3-yl)-4H-1,2,4-triazole-3-carboxamideand5-((S)-2,3-dihydro-1H-inden-1-yl)-N—((S)-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepin-3-yl)-4H-1,2,4-triazole-3-carboxamide

The racemate of5-(2,3-dihydro-1H-inden-1-yl)-N—((S)-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepin-3-yl)-4H-1,2,4-triazole-3-carboxamide(10 mg) was separated by Prep-Chiral-HPLC with the following conditions:Column: CHIRALPAK IA, 2.12×15 cm, 5 μm; Mobile Phase A: Hex:DCM 4.5:1,Mobile Phase B: EtOH; Flow rate: 20 mL/min; Gradient: 50% B to 50% Bover 17.5 min; 220/254 nm; RT1: 10.95 min; RT2: 15.02 min to afford thetitle compounds.

Example 102A (First eluting isomer): ¹H NMR (400 MHz, Methanol-d₄) δ8.14-8.13 (m, 1H), 7.57-7.55 (m, 1H), 7.33-7.31 (m, 1H), 7.31-7.10 (m,3H), 7.09-7.07 (m, 1H), 5.04-4.91 (m, 1H), 4.69-4.61 (m, 2H), 4.47-4.42(m, 1H), 3.18-3.15 (m, 1H), 3.07-3.03 (m, 1H), 2.65-2.63 (m, 1H),2.44-2.39 (m, 1H). LC-MS (Method T): m/z=391.3 [M+H]⁺, 1.133 min.

Example 102B (Second eluting isomer): ¹H NMR (400 MHz, Methanol-d₄) δ8.14-8.13 (m, 1H), 7.57-7.55 (m, 1H), 7.33-7.31 (m, 1H), 7.31-7.10 (m,3H), 7.09-7.07 (m, 1H), 5.04-4.91 (m, 1H), 4.69-4.61 (m, 2H), 4.47-4.42(m, 1H), 3.18-3.15 (m, 1H), 3.07-3.03 (m, 1H), 2.65-2.63 (m, 1H),2.44-2.39 (m, 1H). LC-MS (Method T): m/z=391.3 [M+H]⁺, 1.135 min.

Example 103A and 103B:(R)-5-benzyl-N-(7,9-difluoro-2-oxo-1,2,3,4-tetrahydrospiro[benzo[b]azepine-5,1′-cyclopropan]-3-yl)-4H-1,2,4-triazole-3-carboxamideand(S)-5-benzyl-N-(7,9-difluoro-2-oxo-1,2,3,4-tetrahydrospiro[benzo[b]azepine-5,1′-cyclopropan]-3-yl)-4H-1,2,4-triazole-3-carboxamide

Step 1: Preparation of dimethyl 2-(3,5-difluoro-2-nitrophenyl)malonate

Dimethyl malonate (15 g, 114 mmol) was added dropwise to a stirringmixture of 1,3,5-trifluoro-2-nitrobenzene (10 g, 56 mmol) and potassiumcarbonate (23 g, 168 mmol) in N,N-dimethylformamide (150 mL). Thereaction mixture was stirred overnight at 70° C. and quenched by theaddition of water (50 mL). The resulting solution was extracted withethyl acetate (3×100 mL). The combined organic layers were washed withbrine, dried over anhydrous sodium sulfate, filtered and concentratedunder vacuum. The residue was purified by column chromatography (ethylacetate/petroleum ether, 1/8) to afford the title compound (15 g, 92%)as yellow oil. LC-MS (Method C): m/z=290.0 [M+H]⁺, 1.235 min.

Step 2: Preparation of methyl 2-(3,5-difluoro-2-nitrophenyl)acetate

A solution of lithium chloride (6.3 g, 150 mmol) in water (20 mL) wasadded to a solution of dimethyl 2-(3,5-difluoro-2-nitrophenyl)malonate(15 g, 52 mmol) in dimethyl sulfoxide (50 mL). The reaction mixture wasstirred overnight at 100° C. and quenched by the addition of water (250mL). The resulting solution was extracted with ethyl acetate (3×150 mL).The combined organic layers were washed with brine, dried over anhydroussodium sulfate, filtered and concentrated under vacuum to afford thetitle compound (11 g crude) as a yellow oil, which was used directly inthe next step without further purification.

Step 3: Preparation of methyl1-(3,5-difluoro-2-nitrophenyl)cyclopropanecarboxylate

1,2-Dibromoethane (13 g, 70 mmol) was added dropwise to a stirringsolution of methyl 2-(3,5-difluoro-2-nitrophenyl)acetate (11 g, 48 mmol)and potassium carbonate (20 g, 145 mmol) in N,N-dimethylformamide (50mL). The reaction mixture was stirred overnight at 70° C. and quenchedby the addition of water (250 mL). The resulting solution was extractedwith ethyl acetate (3×250 mL). The combined organic layers were washedwith brine, dried over anhydrous sodium sulfate, filtered andconcentrated under vacuum. The residue was purified by columnchromatography (ethyl acetate/petroleum ether, 1/8) to afford the titlecompound (1.1 g, 9%) as a yellow oil. LC-MS (Method C): m/z=258.1[M+H]⁺, 1.291 min.

Step 4: Preparation of(1-(3,5-difluoro-2-nitrophenyl)cyclopropyl)methanol

A solution of diisobutylaluminium hydride in toluene (1 M, 9.4 mL, 9.4mmol) was added dropwise to a stirring solution of methyl1-(3,5-difluoro-2-nitrophenyl)cyclopropanecar-boxylate (1.1 g, 4.3 mmol)in toluene (30 mL) at −78° C. under nitrogen atmosphere. The reactionmixture was stirred at −78° C. for 2 hours, quenched by the addition ofwater (50 mL) and extracted with ethyl acetate (3×50 mL). The combinedorganic layers were washed with brine, dried over anhydrous sodiumsulfate, filtered and concentrated under vacuum. The residue waspurified by column chromatography (ethyl acetate/petroleum ether, 1/6)to afford the title compound (0.92 g, 94%) as a yellow oil. LC-MS(Method C): m/z=230.1 [M+H]⁺, 1.192 min.

Step 5: Preparation of1-(3,5-difluoro-2-nitrophenyl)cyclopropanecarbaldehyde

Dess-Martin periodinane (3.4 g, 8 mmol) was added to a stirring solutionof (1-(3,5-difluoro-2-nitrophenyl)cyclopropyl)methanol (0.92 g, 4 mmol)in dichloromethane (30 mL). The reaction mixture was stirred at 0° C.for 2 hours, quenched by the addition of water (50 mL) and extractedwith dichloromethane (3×50 mL). The combined organic layers were washedwith brine, dried over sodium sulfate, filtered and concentrated undervacuum. The residue was purified by column chromatography (ethylacetate/petroleum ether, 1/6) to afford the title compound (0.85 mg,92%) as yellow oil.

Step 6: Preparation of (E)-ethyl3-(1-(3,5-difluoro-2-nitrophenyl)cyclopropyl)acrylate

Ethyl (triphenylphosphoranylidene) acetate (1.5 g, 4.3 mmol) was addedto a stirring solution of1-(3,5-difluoro-2-nitrophenyl)cyclopropanecarbaldehyde (800 mg, 3.5mmol) in tetrahydrofuran (50 mL). The reaction mixture was stirredovernight at 50° C., quenched by the addition of water (100 mL) andextracted with dichloromethane (3×100 mL). The combined organic layerswere washed with brine, dried over anhydrous sodium sulfate, filteredand concentrated under vacuum. The residue was purified by columnchromatography (ethyl acetate/petroleum ether, 1/8) to afford the titlecompound (0.64 g, 61%) as a yellow oil. LC-MS (Method C): m/z=298.0[M+H]⁺, 1.382 min.

Step 7. Preparation of ethyl3-(1-(2-amino-3,5-difluorophenyl)cyclopropyl)propanoate

(E)-ethyl 3-(1-(3,5-difluoro-2-nitrophenyl)cyclopropyl)acrylate (640 mg,2.2 mmol) in methanol (30 mL) was hydrogenated in presence of palladiumon carbon (10%, 65 mg) under a hydrogen atmosphere (2-3 atm). Afterstirring overnight at room temperature under a hydrogen atmosphere, thereaction mixture was filtered through Celite. The filtrate wasconcentrated under vacuum to afford the title compound (400 mg crude) asa yellow oil. LC-MS (Method C): m/z=270.1 [M+H]⁺, 1.361 min.

Step 8: Preparation of3-(1-(2-amino-3,5-difluorophenyl)cyclopropyl)propanoic acid

Lithium hydroxide (180 mg, 7.5 mmol) was added to a solution of ethyl3-(1-(2-amino-3,5-difluorophenyl)cyclopropyl)propanoate (400 mg, 1.5mmol) in tetrahydrofuran (30 mL) and water (10 mL). The reaction mixturewas stirred at room temperature overnight. After removal oftetrahydrofuran under reduced pressure, the resulting solution wasadjusted to pH=7 with aqueous hydrochloric acid (1 N, 10 mL). Theresulting solution was extracted with ethyl acetate (3×50 mL). Thecombined organic layers were washed with brine, dried over anhydroussodium sulfate, and filtered. The filtrate was concentrated under vacuumto afford the title compound (320 mg crude) as a yellow oil. LC-MS(Method C): m/z=242.1 [M+H]⁺, 1.143 min.

Step 9: Preparation of7,9-difluoro-3,4-dihydrospiro[benzo[b]azepine-5,1′-cyclopropan]-2(1H)-one

N,N-diisopropylethylamine (515 mg, 4.0 mmol) was added to a mixture of3-(1-(2-amino-3,5-difluorophenyl)cyclopropyl)propanoic acid (320 mg, 1.3mmol) and N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uroniumhexafluorophospate (608 mg, 1.6 mmol) in N,N-dimethylformamide (10 mL).The reaction mixture was stirred at room temperature for 2 hours andquenched by the addition of water (50 mL). The resulting solution wasextracted with ethyl acetate (3×50 mL). The combined organic layers werewashed with brine, dried over anhydrous sodium sulfate, filtered andconcentrated under vacuum. The residue was purified by columnchromatography (ethyl acetate/petroleum ether, 1/6) to afford the titlecompound (270 mg, 91%) as a yellow oil. LC-MS (Method C): m/z=224.1[M+H]⁺, 1.303 min.

Step 10: Preparation of7,9-difluoro-3-iodo-3,4-dihydrospiro[benzo[b]azepine-5,1′-cyclopropan]-2(1H)-one

N,N,N′,N′-tetramethylethylenediamine (418 mg, 3.6 mmol) was added into asolution of7,9-difluoro-3,4-dihydrospiro[benzo[b]azepine-5,1′-cyclopropan]-2(1H)-one(270 mg, 1.2 mmol) in dichloromethane (40 mL) at 0° C. followed byaddition of iodotrimethylsilane (720 mg, 3.6 mmol) dropwise over 20 min.The mixture was stirred for 1 hour at 0° C. and then iodine (457 mg, 1.8mmol) was added into the mixture. After stirring for an additional 1hour at 0° C., the reaction mixture was quenched by the addition ofaqueous sodium thiosulfate (5%, 20 mL) and extracted with ethyl acetate(3×50 mL). The combined organic layers were washed with brine, driedover anhydrous sodium sulfate, and filtered. The filtrate wasconcentrated under vacuum to afford the title compound (410 mg crude) asyellow oil. LC-MS (Method C): m/z=350.1 [M+H]⁺, 1.262 min.

Step 11: Preparation of3-azido-7,9-difluoro-3,4-dihydrospiro[benzo[b]azepine-5,1′-cyclopropan]-2(1H)-one

Sodium azide (117 mg, 1.8 mmol) was added to a solution of7,9-difluoro-3-iodo-3,4-dihydrospiro[benzo[b]azepine-5,1′-cyclopropan]-2(1H)-one(410 mg, 1.2 mmol) in N,N-dimethylformamide (20 mL). The resultingmixture was stirred overnight at room temperature and quenched by theaddition of water (40 mL). The resulting solution was extracted withethyl acetate (3×50 mL). The combined organic layers were washed withbrine, dried over sodium sulfate, and filtered. The filtrate wasconcentrated under vacuum to afford the title compound (260 mg crude) asa yellow oil. LC-MS (Method E): m/z=265.1 [M+H]⁺, 0.875 min.

Step 12: Preparation of3-amino-7,9-difluoro-3,4-dihydrospiro[benzo[b]azepine-5,1′-cyclopropan]-2(1H)-one

Triphenylphosphine (393 mg, 1.5 mmol) was added to a solution of3-azido-7,9-difluoro-3,4-dihydrospiro[benzo[b]azepine-5,1′-cyclopropan]-2(1H)-one(260 mg, 1.0 mmol) in tetrahydrofuran (10 mL) and water (1 mL). Theresulting mixture was stirred overnight at room temperature, dilutedwith water (20 mL) and extracted with dichloromethane (3×50 mL). Thecombined organic layers were washed with brine, dried over anhydroussodium sulfate, filtered and concentrated under vacuum. The residue waspurified by column chromatography (ethyl acetate/petroleum ether, 5/1)to afford the title compound (210 mg, 90%) as a yellow oil. LC-MS(Method C): m/z=239.1 [M+H]⁺, 0.814 min.

Step 13: Preparation of5-benzyl-N-(7,9-difluoro-2-oxo-1,2,3,4-tetrahydrospiro[benzo[b]azepine-5,1′-cyclopropan]-3-yl)-4H-1,2,4-triazole-3-carboxamide

The crude product obtained using Amide Coupling Procedure C was purifiedby Prep-HPLC with the following conditions: Column: XBridge Prep C18 OBDColumn 19×150 mm, 5 μm; Mobile Phase A: water (10 mmol/L NH₄HCO₃),Mobile Phase B: ACN; Flow rate: 30 mL/min; Gradient: 25% B to 55% B over7 min; UV 254 & 220 nm to afford the title compound (30 mg, 26%) as awhite solid. LC-MS (Method O): m/z=423.9 [M+H]⁺, 1.204 min.

Step 14: Preparation of(R)-5-benzyl-N-(7,9-difluoro-2-oxo-1,2,3,4-tetrahydrospiro[benzo[b]azepine-5,1′-cyclopropan]-3-yl)-4H-1,2,4-triazole-3-carboxamide (Example103A) and(S)-5-benzyl-N-(7,9-difluoro-2-oxo-1,2,3,4-tetrahydrospiro[benzo[b]azepine-5,1′-cyclopropan]-3-yl)-4H-1,2,4-triazole-3-carboxamide(Example 103B)

The racemate of5-benzyl-N-(7,9-difluoro-2-oxo-1,2,3,4-tetrahydrospiro[benzo[b]azepine-5,1′-cyclopropan]-3-yl)-4H-1,2,4-triazole-3-carboxamide wasseparated by Prep-Chiral-HPLC with the following conditions: Column:Chiralpak IA, 2×25 cm, 5 μm; Mobile Phase A: hexanes, Mobile Phase B:EtOH; Flow rate: 16 mL/min; Gradient: 55% B to 55% B over 27 min; UV 220& 254 nm; Rt1: 13.94 min; Rt2: 21.44 min to afford the two titlecompounds.

Example 103A (first eluting isomer): ¹H NMR (400 MHz, Methanol-d₄) δ7.33-7.26 (m, 5H), 7.10-6.99 (m, 2H), 4.72-4.62 (m, 1H), 4.17 (s, 2H),3.08-2.99 (m, 1H), 1.63-1.57 (m, 1H), 1.25-1.18 (m, 1H), 1.07-1.01 (m,1H), 0.85-0.77 (m, 1H), 0.59-0.52 (m, 1H). LC-MS (Method O): m/z=423.9[M+H]⁺, 1.204 min.

Example 103B (second eluting isomer): ¹H NMR (400 MHz, Methanol-d₄) δ7.36-7.23 (m, 5H), 7.07-6.98 (m, 2H), 4.73-4.64 (m, 1H), 4.23 (s, 2H),3.07-2.96 (m, 1H), 1.68-1.53 (m, 1H), 1.25-1.18 (m, 1H), 1.06-0.99 (m,1H), 0.84-0.77 (m, 1H), 0.59-0.52 (m, 1H). LC-MS (Method V): m/z=424.2[M+H]⁺, 2.031 min.

Example 104A and 104B:(R)-5-benzyl-N-(2-methyl-5-oxo-2,4,5,6,7,8-hexahydropyrazolo[4,3-b]azepin-6-yl)-4H-1,2,4-triazole-3-carboxamideand(S)-5-benzyl-N-(2-methyl-5-oxo-2,4,5,6,7,8-hexahydropyrazolo[4,3-b]azepin-6-yl)-4H-1,2,4-triazole-3-carboxamide

Step 1: Preparation of ethyl4-(1-methyl-4-nitro-1H-pyrazol-3-yl)butanoate

A solution of (4-ethoxy-4-oxobutyl)zinc(II) bromide in tetrahydrofuran(0.5 M, 41.5 mL, 20.7 mmol) was added to a stirring mixture of3-iodo-1-methyl-4-nitro-1H-pyrazole (4.32 g, 17.1 mmol) anddicyclohexyl(2′,6′-dimethoxybiphenyl-2-yl)phosphine (864 mg, 2.1 mmol)in tetrahydrofuran (50 mL) under nitrogen atmosphere, followed by theaddition of a mixture of palladium diacetate (432 mg, 1.9 mmol) intetrahydrofuran dropwise. The resulting mixture was stirred overnight atroom temperature and concentrated under high vacuum. The residue waspurified by column chromatography (methanol/dichloromethane, 1/99) toafford the title compound (1.7 g, 41.3%) as a yellow oil. LC-MS (MethodE): m/z=242.1 [M+H]⁺, 0.852 min.

Step 2: Preparation of 4-(1-methyl-4-nitro-1H-pyrazol-3-yl)butanoic acid

Lithium hydroxide (339 mg, 14.1 mmol) was added to a mixture of ethyl4-(1-methyl-4-nitro-1H-pyrazol-3-yl)butanoate (1.7 g, 7.05 mmol) intetrahydrofuran (30 mL) and water (10 mL). The reaction mixture wasstirred for 2 hours at room temperature. After removal oftetrahydrofuran under reduced pressure, the pH value of the solution wasadjusted to 6-7 with aqueous hydrochloride acid (1 N, 20 mL). Theresulting solution was extracted with ethyl acetate (3×50 mL). Thecombined organic layers were washed with brine, dried over anhydroussodium sulfate, and filtered. The filtrate was concentrated under highvacuum to afford the title compound (1.2 g crude) as a yellow solid.LC-MS (Method E): m/z=213.9 [M+H]⁺, 0.617 min.

Step 3: Preparation of 4-(4-amino-1-methyl-1H-pyrazol-3-yl)butanoic acid

A solution of 4-(1-methyl-4-nitro-1H-pyrazol-3-yl)butanoic acid (1.2 g,5.61 mmol) in methanol (20 mL) was hydrogenated in the presence ofpalladium on carbon (10%, 120 mg) under a hydrogen atmosphere (2-3 atm).After stirring for 5 hours at room temperature under a hydrogenatmosphere, the reaction mixture was filtered through Celite. Thefiltrate was concentrated under vacuum to afford the title compound (1 gcrude) as a yellow solid. LC-MS (Method C): m/z=184.1 [M+H]⁺, 0.304 min.

Step 4: Preparation of2-methyl-7,8-dihydropyrazolo[4,3-b]azepin-5(2H,4H,6H)-one

N,N-diisopropylethylamine (2.2 g, 17.05 mmol) was added to a stirredmixture of 4-(4-amino-1-methyl-1H-pyrazol-3-yl)butanoic acid (1.0 g,5.46 mmol) and N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uroniumhexafluorophospate (2.5 g, 6.58 mmol) in N,N-dimethylformamide (20 mL).The reaction mixture was stirred for 3 hours at room temperature anddiluted with water (50 mL). The resulting solution was extracted withethyl acetate (3×50 mL). The combined organic layers were washed withbrine, dried over anhydrous sodium sulfate, filtered and concentratedunder vacuum. The residue was purified by column chromatography (ethylacetate/petroleum ether, 1/4) to afford the title compound (560 mg,62.1%) as a yellow solid. LC-MS (Method C): m/z=166.2 [M+H]⁺, 0.331 min.

Step 5: Preparation of6-iodo-2-methyl-7,8-dihydropyrazolo[4,3-b]azepin-5(2H,4H,6H)-one

N¹,N¹,N²,N²-tetramethylethane-1,2-diamine (1.01 g, 8.73 mmol) was addedto a stirring mixture of2-methyl-7,8-dihydropyrazolo[4,3-b]azepin-5(2H,4H,6H)-one (0.48 g, 2.91mmol) in dichloromethane (30 mL) at 0° C. followed by addingiodotrimethylsilane (1.16 g, 5.82 mmol) dropwise over 20 min. Thereaction mixture was stirred for 1 hour at 0° C. Iodine (1.11 g, 4.37mmol) was added to the mixture. The reaction mixture was stirred for anadditional 1 hour at 0° C. and quenched by the addition of aqueoussodium thiosulfate (5%, 20 mL). The resulting solution was stirred for15 minutes and extracted with ethyl acetate (3×50 mL). The combinedorganic layers were washed with brine, dried over anhydrous sodiumsulfate, and filtered. The filtrate was concentrated under vacuum toafford the title compound (550 mg crude) as a yellow solid. LC-MS(Method I): m/z=291.9 [M+H]⁺, 0.522 min.

Step 6: Preparation of6-azido-2-methyl-7,8-dihydropyrazolo[4,3-b]azepin-5(2H,4H,6H)-one

Sodium azide (246 mg, 3.78 mmol) was added to a solution of6-iodo-2-methyl-7,8-dihydropyrazolo[4,3-b]azepin-5(2H,4H,6H)-one (550mg, 1.89 mmol) in N,N-dimethylformamide (4 mL). The reaction mixture wasstirred overnight at 40° C., diluted with water (50 mL) and extractedwith ethyl acetate (3×50 mL). The combined organic layers were washedwith brine, dried over anhydrous sodium sulfate, filtered andconcentrated under reduced pressure to afford the title compound (480 mgcrude) as a brown solid, which was used directly in the next stepwithout further purification. LC-MS (Method I): m/z=207.0 [M+H]⁺, 0.481min.

Step 7: Preparation of6-amino-2-methyl-7,8-dihydropyrazolo[4,3-b]azepin-5(2H,4H,6H)-one

Triphenylphosphine (1.5 g, 7.28 mmol) was added to a solution of6-azido-2-methyl-7,8-dihydropyrazolo[4,3-b]azepin-5(2H,4H,6H)-one (0.48g, 2.18 mmol) in tetrahydrofuran (10 mL) and water (1 mL). The resultingmixture was stirred for 16 hours at room temperature, diluted with water(50 mL) and extracted with dichloromethane (3×50 mL). The combinedorganic layers were washed with brine, dried over anhydrous sodiumsulfate, filtered and concentrated under vacuum. The residue waspurified by column chromatography (methanol/dichloromethane, 3/97) toafford the title compound (300 mg, 70.9%) as a yellow oil. LC-MS (MethodR): m/z=181.3 [M+H]⁺, 0.655 min.

Step 8: Preparation of5-benzyl-N-(2-methyl-5-oxo-2,4,5,6,7,8-hexahydropyrazolo[4,3-b]azepin-6-yl)-4H-1,2,4-triazole-3-carboxamide

The crude product obtained using Amide Coupling Procedure C was purifiedby Prep-HPLC with the following conditions: Column: XSelect CSH Prep C18OBD Column, 5 μm, 19×150 mm; Mobile Phase A: water (0.05% TFA), MobilePhase B: ACN; Flow rate: 20 mL/min; Gradient: 5% B to 47% B over 7 min;UV 254 & 220 nm; Rt: 6.22 min to afford the title compound (50 mg,26.8%) as a white solid. LC-MS (Method Y): m/z=366.0 [M+H]⁺, 0.779 min.

Step 9: Preparation of(R)-5-benzyl-N-(2-methyl-5-oxo-2,4,5,6,7,8-hexahydropyrazolo[4,3-b]azepin-6-yl)-4H-1,2,4-triazole-3-carboxamide(Example 104A) and(S)-5-benzyl-N-(2-methyl-5-oxo-2,4,5,6,7,8-hexahydropyrazolo[4,3-b]azepin-6-yl)-4H-1,2,4-triazole-3-carboxamide(Example 104B)

The racemate of5-benzyl-N-(2-methyl-5-oxo-2,4,5,6,7,8-hexahydropyrazolo[4,3-b]azepin-6-yl)-4H-1,2,4-triazole-3-carboxamide(50 mg, 0.13 mmol) was separated by Prep-Chiral-HPLC with the followingconditions: Column: CHIRAL ART Cellulose-SB, 2×25 cm, 5 μm; Mobile PhaseA: hexane, Mobile Phase B: i-PrOH; Flow rate: 20 mL/min; Gradient: 50% Bto 50% B over 21 min; UV 254 & 220 nm; Rt1: 9.68 min; Rt2: 14.84 min toafford the title compounds:

Example 104A (first eluting isomer): ¹H NMR (400 MHz, DMSO-d₆) δ 14.37(br. s, 1H), 9.86 (s, 1H), 8.39 (br. s, 1H), 7.40 (s, 1H), 7.34-7.22 (m,5H), 4.40-4.35 (m, 1H), 4.11 (s, 2H), 3.74 (s, 3H), 2.90-2.81 (m, 2H),2.26-2.20 (m, 1H), 2.11-1.97 (m, 1H). LC-MS (Method X): m/z=366.2[M+H]⁺, 2.165 min.

Example 104B (second eluting isomer): ¹H NMR (400 MHz, DMSO-d₆) δ 14.37(br. s, 1H), 9.86 (s, 1H), 8.39 (br. s, 1H), 7.40 (s, 1H), 7.34-7.22 (m,5H), 4.40-4.35 (m, 1H), 4.11 (s, 2H), 3.74 (s, 3H), 2.89-2.84 (m, 2H),2.25-2.21 (m, 1H), 2.11-1.97 (m, 1H). LC-MS (Method T): m/z=366.3[M+H]⁺, 0.858 min.

Example 105A and 105B:(S)-5-benzyl-N-(2,4-dimethyl-5-oxo-2,4,5,6,7,8-hexahydropyrazolo[4,3-b]azepin-6-yl)-4H-1,2,4-triazole-3-carboxamideand(R)-5-benzyl-N-(2,4-dimethyl-5-oxo-2,4,5,6,7,8-hexahydropyrazolo[4,3-b]azepin-6-yl)-4H-1,2,4-triazole-3-carboxamide

Step 1: Preparation of6-azido-2,4-dimethyl-7,8-dihydropyrazolo[4,3-b]azepin-5(2H,4H,6H)-one

Iodomethane (664 mg, 4.68 mmol) was added dropwise to a stirred mixtureof 6-azido-2-methyl-7,8-dihydropyrazolo[4,3-b]azepin-5(2H,4H,6H)-one(480 mg, 2.33 mmol) and cesium carbonate (1.5 g, 4.66 mmol) inN,N-dimethylformamide (10 mL). The reaction mixture was stirred for 2hours at room temperature and quenched by the addition of water (50 mL).The resulting solution was extracted with ethyl acetate (3×50 mL). Thecombined organic phases were washed with brine, dried over anhydroussodium sulfate, and filtered. The filtrate was concentrated under vacuumto afford the title compound (480 mg crude) as a brown solid. LC-MS(Method I): m/z=221.0[M+H]⁺, 0.565 min.

Step 2: Preparation of6-amino-2,4-dimethyl-7,8-dihydropyrazolo[4,3-b]azepin-5(2H,4H,6H)-one

Triphenylphosphine (2.44 g, 9.31 mmol) was added to a solution of6-azido-2,4-dimethyl-7,8-dihydropyrazolo[4,3-b]azepin-5(2H,4H,6H)-one(480 mg, 2.18 mmol) in tetrahydrofuran (10 mL) and water (1 mL). Theresulting mixture was stirred for 16 hours at room temperature, dilutedwith water (50 mL) and extracted with dichloromethane (3×50 mL). Thecombined organic layers were washed with brine, dried over anhydroussodium sulfate, filtered and concentrated to dryness under vacuum. Theresidue was purified by column chromatography (methanol/dichloromethane,3/97) to afford the title compound (300 mg, 71%) as a yellow oil. LC-MS(Method I): m/z=195.0 [M+H]⁺, 0.168 min.

Step 3: Preparation of5-benzyl-N-(2,4-dimethyl-5-oxo-2,4,5,6,7,8-hexahydropyrazolo[4,3-b]azepin-6-yl)-4H-1,2,4-triazole-3-carboxamide

The crude product obtained using Amide Coupling Procedure C was purifiedby Prep-HPLC with the following conditions: Column: XBridge C18 OBD PrepColumn, 100 Å, 5 μm, 19 mm×250 mm; Mobile Phase A: water (0.1% formicacid), Mobile Phase B: ACN; Flow rate: 20 mL/min; Gradient: 15% B to 30%B over 10 min; UV 254 & 220 nm; Rt: 7 min to afford the title compound(50 mg, 26.8%) as a white solid. LC-MS (Method Q): m/z=380.4 [M+H]⁺,0.786 min.

Step 4: Preparation of(S)-5-benzyl-N-(2,4-dimethyl-5-oxo-2,4,5,6,7,8-hexahydropyrazolo[4,3-b]azepin-6-yl)-4H-1,2,4-triazole-3-carboxamide(Example 105A) and(R)-5-benzyl-N-(2,4-dimethyl-5-oxo-2,4,5,6,7,8-hexahydropyrazolo[4,3-b]azepin-6-yl)-4H-1,2,4-triazole-3-carboxamide(Example 105B)

The racemate of5-benzyl-N-(2,4-dimethyl-5-oxo-2,4,5,6,7,8-hexahydropyrazolo[4,3-b]azepin-6-yl)-4H-1,2,4-triazole-3-carboxamide(50 mg, 0.13 mmol) was separated by Prep-Chiral-HPLC with the followingconditions: Column: CHIRALPAK IC, 2×25 cm, 5 μm; Mobile Phase A:hexane:DCM=4.5:1, Mobile Phase B: EtOH; Flow rate: 16 mL/min; Gradient:50% B to 50% B over 21 min; UV 220 & 254 nm; Rt1: 8.88 min; Rt2: 16.76min to afford the title compounds:

Example 105A (first eluting isomer): ¹H NMR (400 MHz, DMSO-d₆) δ 14.35(br. s, 1H), 8.32 (br. s, 1H), 7.83 (s, 1H), 7.34-7.22 (m, 5H),4.53-4.45 (m, 1H), 4.11 (s, 2H), 3.79 (s, 3H), 3.19 (s, 3H), 2.85-2.66(m, 2H), 2.35-2.31 (m, 1H), 2.30-2.26 (m, 1H). LC-MS (Method T):m/z=380.2 [M+H]⁺, 0.958 min.

Example 105B (second eluting isomer): ¹H NMR (400 MHz, DMSO-d₆) δ 14.29(br. s, 1H), 8.30 (br. s, 1H), 7.83 (s, 1H), 7.34-7.22 (m, 5H),4.52-4.46 (m, 1H), 4.11 (s, 2H), 3.79 (s, 3H), 3.19 (s, 3H), 2.85-2.68(m, 2H), 2.35-2.31 (m, 1H), 2.30-2.27 (m, 1H). LC-MS (Method T):m/z=380.2 [M+H]⁺, 0.953 min.

Example 106:(S)—N-(5-methyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepin-3-yl)-5-(1-phenylcyclopropyl)-4H-1,2,4-triazole-3-carboxamide

The crude product obtained using the procedure described in Example 54was purified by Prep-HPLC with the following conditions: Column: XSelectCSH Prep C18 OBD Column, 5 m, 19×150 mm; Mobile Phase A: water (0.1%formic acid); Mobile Phase B: ACN; Flow rate: 20 mL/min; Gradient: 30% Bto 60% B over 7 min; Detector, UV 254 & 220 nm; Rt: 5.47 min to affordthe title compound. ¹H NMR (400 MHz, DMSO-d₆) δ 14.11 (s, 1H), 8.49 (d,J=7.9 Hz, 1H), 8.37 (dd, J=4.8, 1.5 Hz, 1H), 7.71 (dd, J=8.0, 1.5 Hz,1H), 7.40-7.22 (m, 6H), 4.92-4.66 (m, 2H), 4.56-4.55 (m, 1H), 3.36 (s,3H), 1.52-1.27 (m, 4H). LC-MS (Method O): m/z=405.0 [M+H]⁺, 1.126 min.

Example 107A and 107B:(R)-5-benzyl-N-(9-methyl-8-oxo-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]azepin-7-yl)-4H-1,2,4-triazole-3-carboxamideand(S)-5-benzyl-N-(9-methyl-8-oxo-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]azepin-7-yl)-4H-1,2,4-triazole-3-carboxamide

Step 1: Preparation of (E)-6,7-dihydroquinolin-8(5H)-one oxime

Hydroxylamine hydrochloride (1.4 g, 20.3 mmol) was added to a solutionof 6,7-dihydroquinolin-8(5H)-one (1.5 g, 10.2 mmol) and sodium hydroxide(1.2 g, 30.0 mmol) in ethanol (20 mL) and water (10 mL). The resultingmixture was stirred at 80° C. for 2 hours. The reaction mixture wasdiluted with water (50 mL) and extracted with dichloromethane (3×80 mL).The combined organic layers were washed with brine, dried over anhydroussodium sulfate, filtered and concentrated under vacuum. The residue waspurified by column chromatography (ethyl acetate/petroleum ether, 1/20)to afford the title compound (1.4 g, 86.4%) as a white solid. LC-MS(Method E): m/z=163.1 [M+H]⁺, 0.362 min.

Step 2: Preparation of (E)-6,7-dihydroquinolin-8(5H)-oneO-methylsulfonyl oxime

Triethylamine (3.5 g, 30.6 mmol) and methanesulfonyl chloride (0.74 g,6.4 mmol) were added to a solution of (E)-6,7-dihydroquinolin-8(5H)-oneoxime (1.4 g, 8.64 mmol) in dichloromethane (20 mL). The reactionmixture was stirred at room temperature for 2 hours, diluted with water(30 mL) and extracted with ethyl acetate (3×50 mL). The combined organiclayers were washed with brine, dried with anhydrous sodium sulfate andconcentrated under vacuum. The residue was purified by columnchromatography (ethyl acetate/petroleum ether, 1/5) to afford the titlecompound (1.7 g, 82%) as a yellow solid. LC-MS (Method C): m/z=241.0[M+H]⁺, 0.810 min.

Step 3: Preparation of 6,7-dihydro-5H-pyrido[2,3-b]azepin-8(9H)-one

Potassium acetate (5 g, 51 mmol) was added to a solution of(E)-6,7-dihydroquinolin-8(5H)-one O-methylsulfonyl oxime (1.7 g, 7 mmol)in ethanol (40 mL) and water (20 mL). The reaction mixture was stirredovernight at 110° C. and concentrated under reduced pressure. Theresidue was diluted with water (30 mL) and extracted with ethyl acetate(3×50 mL). The combined organic layers were washed with brine, driedover anhydrous sodium sulfate, filtered and concentrated under vacuum.The residue was purified by column chromatography (ethylacetate/petroleum ether, 1/5) to afford the title compound (1.0 g, 87%)as a yellow solid. LC-MS (Method C): m/z=162.8 [M+H]⁺, 0.612 min.

Step 4: Preparation of9-methyl-6,7-dihydro-5H-pyrido[2,3-b]azepin-8(9H)-one

Iodomethane (1.0 g, 0.70 mmol) was added dropwise to a stirring mixtureof 6,7-dihydro-5H-pyrido[2,3-b]azepin-8(9H)-one (1.0 g, 0.60 mmol) andcesium carbonate (3.0 g, 0.92 mmol) in N,N-dimethylformamide (20 mL).The reaction mixture was stirred at room temperature overnight, quenchedby the addition of water (50 mL) and extracted with ethyl acetate (3×60mL). The combined organic layers were washed with brine, dried overanhydrous sodium sulfate, filtered and concentrated under vacuum. Theresidue was purified by column chromatography (ethyl acetate/petroleumether, 1/30) to afford the title compound (0.97 g, 89.8%) as a yellowsolid. LC-MS (Method C): m/z=177.1 [M+H]⁺, 1.192 min.

Step 5: Preparation of7-iodo-9-methyl-6,7-dihydro-5H-pyrido[2,3-b]azepin-8(9H)-one

N¹,N¹,N²,N²-tetramethylethane-1,2-diamine (1.9 g, 16.4 mmol) was addedto a stirring mixture of9-methyl-6,7-dihydro-5H-pyrido[2,3-b]azepin-8(9H)-one (0.97 g, 5.5 mmol)in dichloromethane (100 mL) at 0° C. followed by the addition ofiodotrimethylsilane (3.3 g, 16.5 mmol) over 20 minutes. The reactionmixture was stirred for 1 hour at 0° C. After adding iodine (4.2 g, 16.5mmol), the reaction mixture was stirred for an additional 4 hours atroom temperature before quenching by the addition of aqueous sodiumthiosulfate (5%, 30 mL). The resulting solution was stirred for 15minutes and extracted with ethyl acetate (3×100 mL). The combinedorganic phases were washed with brine, dried over anhydrous sodiumsulfate, filtered and concentrated under vacuum. The residue waspurified by column chromatography (ethyl acetate/petroleum ether, 1/30)to afford the title compound (1.5 g, 89.8%) as a white solid. LC-MS(Method C): m/z=303.0 [M+H]⁺, 1.350 min.

Step 6: Preparation of7-azido-9-methyl-6,7-dihydro-1H-pyrido[2,3-b]azepin-8(9H)-one

Sodium azide (650 mg, 10.0 mmol) was added to a solution of7-iodo-9-methyl-6,7-dihydro-5H-pyrido[2,3-b]azepin-8(9H)-one (1.5 g, 4.9mmol) in N,N-dimethylformamide (10 mL). The reaction mixture was stirredfor 5 hours at room temperature, diluted with water (30 mL) andextracted with ethyl acetate (3×30 mL). The combined organic layers werewashed with brine, dried over anhydrous sodium sulfate, filtered andconcentrated under vacuum. The residue was purified by columnchromatography (methanol/dichloromethane, 1/10) to afford the titlecompound (900 mg, 84%) as a white solid. LC-MS (Method C): m/z=218.2[M+H]⁺, 0.586 min.

Step 7. Preparation of7-amino-6,7-dihydro-1H-pyrido[2,3-b]azepin-8(9H)-one

Triphenylphosphine (1.6 g, 6.1 mmol) was added to a solution of7-azido-9-methyl-6,7-dihydro-5H-pyrido[2,3-b]azepin-8(9H)-one (0.9 g,4.1 mmol) in tetrahydrofuran (10 mL) and water (10 mL). The reactionmixture was stirred at room temperature overnight, diluted with water(30 mL) and extracted with ethyl acetate (3×50 mL). The combined organiclayers were washed with brine, dried over anhydrous sodium sulfate,filtered and concentrated under vacuum. The residue was purified bycolumn chromatography (methanol/dichloromethane, 1/10) to afford thetitle compound (0.65 g, 82%) as a white solid. LC-MS (Method C):m/z=192.1 [M+H]⁺, 0.386 min.

Step 8: Preparation of5-benzyl-N-(9-methyl-8-oxo-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]azepin-7-yl)-4H-1,2,4-triazole-3-carboxamide

N,N-diisopropylethylamine (201.2 mg, 1.56 mmol) was added to a mixtureof 5-benzyl-4H-1,2,4-triazole-3-carboxylic acid (104.6 mg, 0.52 mmol),7-amino-9-methyl-6,7-dihydro-5H-pyrido[2,3-b]azepin-8(9H)-one (100 mg,0.52 mmol), N-(3-dimethylaminopropyl))-N′-ethylcarbodiimidehydrochloride (119.6 mg, 0.62 mmol) and 1-hydroxybenzotriazole (84.2 mg,0.62 mmol) in N,N-dimethylformamide (4 mL). The reaction mixture wasstirred overnight at room temperature, diluted with water (30 mL) andextracted with ethyl acetate (3×50 mL). The combined organic layers werewashed with brine, dried over anhydrous sodium sulfate, filtered andconcentrated under vacuum. The residue was purified by Prep-HPLC withthe following conditions: Column: XBridge Shield RP18 OBD Column, 5 μm,19×150 mm; Mobile Phase A: water (10 mmol/L NH₄HCO₃), Mobile Phase B:ACN; Flow rate: 20 mL/min; Gradient: 10% B to 35% B over 11 min; UV 254& 220 nm; Rt: 10 min to afford the title compound (50 mg, 25%) as awhite solid. LC-MS (Method D): m/z=377.2 [M+H]⁺, 1.551 min.

Step 9: Preparation of(R)-5-benzyl-N-(9-methyl-8-oxo-6,7,8,9-tetrahydro-1H-pyrido[2,3-b]azepin-7-yl)-4H-1,2,4-triazole-3-carboxamide(Example 107A) and(S)-5-benzyl-N-(9-methyl-8-oxo-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]azepin-7-yl)-4H-1,2,4-triazole-3-carboxamide(Example 107B)

The racemate of5-benzyl-N-(9-methyl-8-oxo-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]azepin-7-yl)-4H-1,2,4-triazole-3-carboxamide(50 mg, 0.14 mmol) was separated by Prep-Chiral-HPLC with the followingconditions: Column: Chiralpak ID-2, 2×25 cm, 5 μm; Mobile Phase A:hexane, Mobile Phase B: MeOH:EtOH=1:1; Flow rate: 17 mL/min; Gradient:60% B to 60% B over 23 min; UV 220 & 254 nm; Rt1: 8.53 min; Rt2: 18.27min to afford the title compounds:

Example 107A (first eluting isomer): ¹H NMR (300 MHz, DMSO-d₆) δ 14.35(br. s, 1H), 8.52-8.42 (m, 2H), 7.82-7.79 (m, 1H), 7.34-7.21 (m, 6H),4.35-4.26 (m, 1H), 4.10 (s, 2H), 3.34 (s, 3H), 2.75-2.62 (m, 2H),2.41-2.16 (m, 2H). LC-MS (Method D): m/z=377.2 [M+H]⁺, 1.551 min.

Example 107B (second eluting isomer): ¹H NMR (300 MHz, DMSO-d₆) δ 14.35(br. s, 1H), 8.45-8.41 (m, 2H), 7.83-7.79 (m, 1H), 7.35-7.15 (m, 6H),4.35-4.23 (m, 1H), 4.10 (s, 2H), 3.34 (s, 3H), 2.75-2.61 (m, 2H),2.50-2.20 (m, 2H). LC-MS (Method D): m/z=377.2 [M+H]⁺, 1.546 min.

Example 108:(S)-2-benzyl-N-(5-methyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepin-3-yl)-1H-imidazole-5-carboxamide

Step 1: Preparation of (Z)—N′-hydroxy-2-phenylacetimidamide

Sodium bicarbonate (1.44 g, 17.1 mmol) was added to a mixture of2-phenylacetonitrile (1.0 g, 8.54 mmol) and hydroxylamine hydrochloride(1.19 g, 17.1 mmol) in ethanol (15 mL) and water (5.0 mL). The reactionmixture was stirred at 80° C. overnight, diluted with water (50 mL) andextracted with ethyl acetate (3×50 mL). The combined organic layers werewashed with brine, dried over anhydrous sodium sulfate and concentratedunder vacuum. The residue was purified by column chromatography(methanol/dichloromethane, 5/95) to afford the title compound (1.15 g,90%) as a white solid. MS (Method I): m/z=151.1 [M+H]⁺, 0.194 min.

Step 2: Preparation of ethyl 2-benzyl-1H-imidazole-5-carboxylate

A reaction mixture of (Z)—N′-hydroxy-2-phenylacetimidamide (1.0 g, 6.67mmol) and ethyl propiolate (1.96 g, 20 mmol) in ethanol (20 mL) wasstirred at 80° C. overnight. Diphenylether (50 mL) was added to themixture and stirred at 130° C. for 2 hours. The reaction mixture wasquenched by the addition of water (50 mL) and extracted with ethylacetate (3×50 mL). The combined organic layers were washed with brine,dried over anhydrous sodium sulfate, filtered and concentrated undervacuum. The residue was purified by column chromatography(methanol/dichloromethane, 1/99) to afford the title compound (650 mg,43%) as a gray solid. LC-MS (Method L): m/z=231.1 [M+H]⁺, 1.197 min.

Step 3: Preparation of(S)-2-benzyl-N-(5-methyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepin-3-yl)-1H-imidazole-5-carboxamide

The crude product obtained using the procedure described in Example 54was purified by Prep-HPLC with the following conditions: Column: XBridgeShield RP18 OBD Column, 5 μm, 19×150 mm; Mobile Phase A: water (10mmol/L NH₄HCO₃), Mobile Phase B: ACN; Flow rate: 20 mL/min; Gradient:20% B to 45% B over 7 min; UV 254 & 220 nm; Rt: 6 min to afford thetitle compound. ¹H NMR (400 MHz, DMSO-d₆) δ 12.41 (s, 1H), 8.36 (dd,J=4.8, 1.6 Hz, 1H), 8.01 (d, J=8.0 Hz, 1H), 7.71 (dd, J=8.0, 1.6 Hz,1H), 7.57 (d, J=2.1 Hz, 1H), 7.38-7.17 (m, 6H), 4.90-4.76 (m, 1H), 4.64(dd, J=11.5, 9.8 Hz, 1H), 4.54-4.45 (m, 1H), 4.02 (s, 2H), 3.36 (s, 3H).LC-MS (Method O): m/z=378.0 [M+H]⁺, 1.047 min.

Example 109A and 109B:(S)-1-benzyl-N-(2,4-dimethyl-5-oxo-2,4,5,6,7,8-hexahydropyrazolo[4,3-b]azepin-6-yl)-4-fluoro-1H-pyrazole-3-carboxamideand(R)-1-benzyl-N-(2,4-dimethyl-5-oxo-2,4,5,6,7,8-hexahydropyrazolo[4,3-b]azepin-6-yl)-4-fluoro-1H-pyrazole-3-carboxamide

Step 1: Preparation of1-benzyl-N-(2,4-dimethyl-5-oxo-2,4,5,6,7,8-hexahydropyrazolo[4,3-b]azepin-6-yl)-4-fluoro-1H-pyrazole-3-carboxamide

The crude product obtained using Amide Coupling Procedure C was purifiedby Prep-HPLC with the following conditions: Column: XBridge Shield RP18OBD Column, 5 μm, 19×150 mm; Mobile Phase A: water (10 mmol/L NH₄HCO₃),Mobile Phase B: ACN; Flow rate: 20 mL/min; Gradient: 20% B to 50% B over7 min; UV 254 & 220 nm; Rt: 6 min to afford the title compound (80 mg,55.6%) as a white solid. LC-MS (Method Q): m/z=397.4 [M+H]⁺, 1.115 min.

Step 2: Preparation of(S)-1-benzyl-N-(2,4-dimethyl-5-oxo-2,4,5,6,7,8-hexahydropyrazolo[4,3-b]azepin-6-yl)-4-fluoro-1H-pyrazole-3-carboxamide(Example 109A) and(R)-1-benzyl-N-(2,4-dimethyl-5-oxo-2,4,5,6,7,8-hexahydropyrazolo[4,3-b]azepin-6-yl)-4-fluoro-1H-pyrazole-3-carboxamide(Example 109B)

The racemate of1-benzyl-N-(2,4-dimethyl-5-oxo-2,4,5,6,7,8-hexahydropyrazolo[4,3-b]azepin-6-yl)-4-fluoro-1H-pyrazole-3-carboxamide(80 mg, 0.20 mmol) was separated by Prep-Chiral-HPLC with the followingconditions: Column: Lux 5 u Cellulose-3, AXIA Packed, 2.12×25 cm, 5 μm;Mobile Phase A: hexane, Mobile Phase B: EtOH; Flow rate: 20 mL/min;Gradient: 40% B to 40% B over 15 min; UV 254 & 220 nm; Rt1: 9.89 min;Rt2: 12.58 min to afford the title compounds:

Example 109A (first eluting isomer): ¹H NMR (400 MHz, DMSO-d₆) δ 8.13(d, J=4.4 Hz, 1H), 7.92 (d, J=7.2 Hz, 1H), 7.83 (s, 1H), 7.40-7.31 (m,3H), 7.31-7.28 (m, 2H), 5.33 (s, 2H), 4.50-4.44 (m, 1H), 3.78 (s, 3H),3.18 (s, 3H), 2.84-2.77 (m, 1H), 2.75-2.67 (m, 1H), 2.33-2.24 (m, 1H),2.16-2.04 (m, 1H). LC-MS (Method T): m/z=397.2 [M+H]⁺, 1.155 min.

Example 109B (second eluting isomer): ¹H NMR (400 MHz, DMSO-d₆) δ 8.13(d, J=4.4 Hz, 1H), 7.93 (d, J=7.2 Hz, 1H), 7.83 (s, 1H), 7.40-7.31 (m,3H), 7.31-7.26 (m, 2H), 5.33 (s, 2H), 4.51-4.42 (m, 1H), 3.78 (s, 3H),3.18 (s, 3H), 2.87-2.63 (m, 2H), 2.35-2.21 (m, 1H), 2.18-2.03 (m, 1H).LC-MS (Method T): m/z=397.2 [M+H]⁺, 1.154 min.

Example 110A and 110B:5-benzyl-N-((1aR,2R,8bS)-3-oxo-1,1a,2,3,4,8b-hexahydrocyclopropa[d]pyrido[2,3-b]azepin-2-yl)-4H-1,2,4-triazole-3-carboxamideand5-benzyl-N-((1aS,2S,8bR)-3-oxo-1,1a,2,3,4,8b-hexahydrocyclopropa[d]pyrido[2,3-b]azepin-2-yl)-4H-1,2,4-triazole-3-carboxamide

Step 1: Preparation of5-benzyl-N-(cis-3-oxo-1,1a,2,3,4,8b-hexahydrocyclopropa[d]pyrido[2,3-b]azepin-2-yl)-4H-1,2,4-triazole-3-carboxamide

The crude product obtained using Amide Coupling Procedure C was purifiedby Prep-TLC (ethyl acetate/petroleum ether, 1/3) to afford the titlecompound (20 mg, 26.7%) as a yellow solid. LC-MS (Method I): m/z=375.2[M+H]⁺, 1.007 min.

Step 2: Preparation of5-benzyl-N-((1aR,2R,8bS)-3-oxo-1,1a,2,3,4,8b-hexahydrocyclopro-pa[d]pyrido[2,3-b]azepin-2-yl)-4H-1,2,4-triazole-3-carboxamide(Example 110A) and5-ben-zyl-N-((1aS,2S,8bR)-3-oxo-1,1a,2,3,4,8b-hexahydrocyclopropa[d]pyrido[2,3-b]azepin-2-yl)-4H-1,2,4-triazole-3-carboxamide(Example 110B)

The racemate of5-benzyl-N-(cis-3-oxo-1,1a,2,3,4,8b-hexahydrocyclopropa[d]pyrido[2,3-b]azepin-2-yl)-4H-1,2,4-triazole-3-carboxamide (20 mg, 0.053 mmol)was separated by Prep-Chiral-HPLC with the following conditions: Column:CHIRAL ART Cellulose-SB, 2×25 cm, 5 μm; Mobile Phase A: hexane, MobilePhase B: EtOH; Flow rate: 20 mL/min; Gradient: 30% B to 30% B over 20min; UV 254 & 220 nm; Rt1: 12.8 min; Rt2: 16.08 min to afford the titlecompounds:

Example 110A (first eluting isomer): ¹H NMR (400 MHz, CD₃OD-d₄) δ 8.24(dd, J=4.8, 1.6 Hz, 1H), 7.91 (dd, J=7.6, 1.6 Hz, 1H), 7.38-7.16 (m,6H), 4.84 (s, 1H), 4.17 (s, 2H), 2.25-2.21 (m, 1H), 2.15-2.09 (m, 1H),1.62-1.57 (m, 1H), 1.16-1.12 (m, 1H). LC-MS (Method J): m/z=375.2[M+H]⁺, 1.007 min.

Example 110B (second eluting isomer): ¹H NMR (300 MHz, CD₃OD-d₄) δ 8.23(dd, J=4.8, 1.8 Hz, 1H), 7.90 (dd, J=7.5, 1.8 Hz, 1H), 7.39-7.13 (m,6H), 4.84 (s, 1H), 4.18 (s, 2H), 2.19-2.09 (m, 2H), 1.64-1.55 (m, 1H),1.17-1.10 (m, 1H). LC-MS (Method F): m/z=374.9 [M+H]⁺, 0.919 min.

Example 111A and 111B:(R)-1-benzyl-4-fluoro-N-(9-methyl-8-oxo-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]azepin-7-yl)-1H-pyrazole-3-carboxamideand(S)-1-benzyl-4-fluoro-N-(9-methyl-8-oxo-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]azepin-7-yl)-1H-pyrazole-3-carboxamide

Step 1 Preparation of1-benzyl-4-fluoro-N-(9-methyl-8-oxo-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]azepin-7-yl)-1H-pyrazole-3-carboxamide

N,N-diisopropylethylamine (201.2 mg, 1.56 mmol) was added to a mixtureof 1-benzyl-4-fluoro-1H-pyrazole-3-carboxylic acid (104.6 mg, 0.52mmol), 7-amino-9-methyl-6,7-dihydro-5H-pyrido[2,3-b]azepin-8(9H)-one(100 mg, 0.52 mmol), N-(3-dimethylaminopropyl))-N′-ethylcarbodiimidehydrochloride (119.6 mg, 0.62 mmol) and 1-hydroxybenzotriazole (84.2 mg,0.62 mmol) in N,N-dimethylformamide (3 mL). The reaction mixture wasstirred overnight at room temperature, diluted with water (10 mL) andextracted with ethyl acetate (3×10 mL). The combined organic layers werewashed with brine, dried over anhydrous sodium sulfate, filtered andconcentrated under vacuum. The crude product obtained using AmideCoupling Procedure C was purified by Prep-HPLC with the followingconditions: Column: XSelect CSH Prep C18 OBD Column, 5 μm, 19×150 mm;Mobile Phase A: water (0.1% formic acid), Mobile Phase B: ACN; Flowrate: 20 mL/min; Gradient: 35% B to 55% B over 7 min; UV 254 & 220 nm;Rt: 5.6 min to afford the title compound (32 mg, 25.4%) as a whitesolid. LC-MS (Method D): m/z=394.2[M+H]⁺, 1.571 min.

Step 2: Preparation of(R)-1-benzyl-4-fluoro-N-(9-methyl-8-oxo-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]azepin-7-yl)-1H-pyrazole-3-carboxamide(Example 111A) and(S)-1-benzyl-4-fluoro-N-(9-methyl-8-oxo-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]azepin-7-yl)-1H-pyrazole-3-carboxamide(Example 111B)

The racemate of1-benzyl-4-fluoro-N-(9-methyl-8-oxo-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]azepin-7-yl)-1H-pyrazole-3-carboxamide(32 mg, 0.081 mmol) was separated by Prep-Chiral-HPLC with the followingconditions: Column: CHIRAL ART Cellulose-SB, 2×25 cm, 5 μm; Mobile PhaseA: hexane, Mobile Phase B: EtOH; Flow rate: 20 mL/min; Gradient: 30% Bto 30% B over 15 min; UV 254 & 220 nm; Rt1: 11.47 min; Rt2: 13.24 min toafford the title compounds:

Example 111A (first eluting isomer): ¹H NMR (300 MHz, DMSO-d₆) δ8.42-8.40 (m, 1H), 8.10-8.02 (m, 2H), 7.80-7.77 (m, 1H), 7.39-7.24 (m,6H), 5.31 (s, 2H), 4.32-4.23 (m, 1H), 3.33 (s, 3H), 2.78-2.60 (m, 2H),2.38-2.25 (m, 2H). LC-MS (Method D): m/z=394.2 [M+H]⁺, 1.571 min.

Example 111B (second eluting isomer): ¹H NMR (300 MHz, DMSO-d₆) δ8.42-8.40 (m, 1H), 8.10-8.02 (m, 2H), 7.80-7.77 (m, 1H), 7.39-7.24 (m,6H), 5.31 (s, 2H), 4.32-4.23 (m, 1H), 3.32 (s, 3H), 2.72-2.66 (m, 2H),2.39-2.26 (m, 2H). LC-MS (Method D): m/z=394.2 [M+H]⁺, 1.570 min.

Example 112:5-benzyl-N-((2R,3S)-2,5-dimethyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepin-3-yl)isoxazole-3-carboxamide

The crude product obtained using Amide Coupling Procedure C was purifiedby Prep-HPLC with the following conditions: Column: XBridge C18 OBD PrepColumn, 5 μm, 19×250 mm; Mobile Phase A: water (10 mmol/L NH₄HCO₃),Mobile Phase B: ACN; Flow rate: 20 mL/min; Gradient: 30% B to 60% B in 7min; UV 254 & 220 nm; Rt: 7 min to afford the title compound. ¹H NMR(400 MHz, DMSO-d₆) δ 8.35 (dd, J=4.7, 1.5 Hz, 1H), 8.27 (d, J=7.0 Hz,1H), 7.73 (dd, J=7.9, 1.5 Hz, 1H), 7.39-7.23 (m, 6H), 6.61 (s, 1H),4.99-4.87 (m, 2H), 4.22 (s, 2H), 3.39 (s, 3H), 1.36 (d, J=6.2 Hz, 3H).LC-MS (Method X): m/z=393.2 [M+H]⁺, 3.187 min.

Example 113:(S)—N-(1-methyl-2-oxo-1,2,3,4-tetrahydropyrido[3,4-b][1,4]oxazepin-3-yl)-5-(1-phenylcyclopropyl)-4H-1,2,4-triazole-3-carboxamide

The crude product obtained using the procedure described in Example 54was purified by Prep-HPLC with the following conditions: Column: XBridgeShield RP18 OBD Column, 5 μm, 19×150 mm; Mobile Phase A: water (0.05%TFA), Mobile Phase B: ACN; Flow rate: 20 mL/min; Gradient: 10% B to 40%B over 7 min; UV 254 & 220 nm; Rt: 6 min to afford the title compound.¹H NMR (400 MHz, DMSO-d₆) δ 14.11 (s, 1H), 8.91-8.36 (m, 3H), 7.53 (d,J=5.3 Hz, 1H), 7.33 (m, 5H), 4.94-4.82 (m, 1H), 4.82-4.70 (m, 1H), 4.51(dd, J=9.6, 7.2 Hz, 1H), 3.32 (s, 3H), 1.59-1.20 (m, 4H). LC-MS (MethodO): m/z=405.0 [M+H]⁺, 1.127 min.

Example 114A and 114B:(S)-1-benzyl-N-(1,4-dimethyl-5-oxo-1,4,5,6,7,8-hexahydropyrazolo[4,3-b]azepin-6-yl)-4-fluoro-1H-pyrazole-3-carboxamideand(R)-1-benzyl-N-(1,4-dimethyl-5-oxo-1,4,5,6,7,8-hexahydropyrazolo[4,3-b]azepin-6-yl)-4-fluoro-1H-pyrazole-3-carboxamide

Step 1: Preparation of1-benzyl-N-(1,4-dimethyl-5-oxo-1,4,5,6,7,8-hexahydropyrazolo[4,3-b]azepin-6-yl)-4-fluoro-1H-pyrazole-3-carboxamide

The crude product obtained using Amide Coupling Procedure C was purifiedby Prep-HPLC with the following conditions: Column: XBridge Prep PhenylOBD Column 19×150 mm 5 μm; Mobile Phase A: water (10 mmol/L NH₄HCO₃),Mobile Phase B: ACN; Flow rate: 20 mL/min; Gradient: 25% B to 50% B over7 min; UV 254 & 220 nm; Rt: 6 min to afford the title compound (50 mg,48.6%) as a white solid. LC-MS (Method C): m/z=397.2 [M+H]⁺, 1.512 min.

Step 2: Preparation of(S)-1-benzyl-N-(1,4-dimethyl-5-oxo-1,4,5,6,7,8-hexahydropyrazolo[4,3-b]azepin-6-yl)-4-fluoro-1H-pyrazole-3-carboxamide(Example 114A) and(R)-1-benzyl-N-(1,4-dimethyl-5-oxo-1,4,5,6,7,8-hexahydropyrazolo[4,3-b]azepin-6-yl)-4-fluoro-1H-pyrazole-3-carboxamide(Example 114B)

The racemate of1-benzyl-N-(1,4-dimethyl-5-oxo-1,4,5,6,7,8-hexahydropyrazolo[4,3-b]azepin-6-yl)-4-fluoro-1H-pyrazole-3-carboxamide(50 mg, 0.13 mmol) was separated by Prep-Chiral-HPLC with the followingconditions: Column: CHIRAL ART Cellulose-SB, 2×25 cm, 5 μm; Mobile PhaseA: hexane, Mobile Phase B: EtOH; Flow rate: 20 mL/min; Gradient: 50% Bto 50% B over 18 min; UV 254 & 220 nm; Rt1: 12.54 min; Rt2: 15.41 min.to afford the title compounds:

Example 114A (first eluting isomer): ¹H NMR (400 MHz, DMSO-d₆) δ 8.14(d, J=4.0 Hz, 1H), 8.07 (d, J=6.4 Hz, 1H), 7.50 (s, 1H), 7.41-7.27 (m,5H), 5.34 (s, 2H), 4.43-4.37 (m, 1H), 3.74 (s, 3H), 3.24 (s, 3H),3.06-2.96 (m, 1H), 2.91-2.84 (m, 1H), 2.30-2.23 (m, 1H), 2.10-1.99 (m,1H). LC-MS (Method D): m/z=397.1 [M+H]⁺, 1.500 min.

Example 114B (second eluting isomer): ¹H NMR (400 MHz, DMSO-d₆) δ 8.14(d, J=4.4 Hz, 1H), 8.07 (d, J=6.8 Hz, 1H), 7.50 (s, 1H), 7.41-7.26 (m,5H), 5.34 (s, 2H), 4.43-4.37 (m, 1H), 3.74 (s, 3H), 3.24 (s, 3H),3.06-2.96 (m, 1H), 2.91-2.83 (m, 1H), 2.30-2.22 (m, 1H), 2.10-1.99 (m,1H). LC-MS (Method D): m/z=397.1 [M+H]⁺, 1.514 min.

Example 115:(S)-4-fluoro-1-(4-fluorobenzyl)-N-(5-methyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepin-3-yl)-1H-pyrazole-3-carboxamide

Step 1: Preparation of4-fluoro-1-(4-fluorobenzyl)-1H-pyrazole-3-carboxylic acid

Sodium hydride (60%, 152 mg, 3.8 mmol) was added to a solution of methyl4-fluoro-1H-pyrazole-3-carboxylate (200 mg, 1.27 mmol) inN,N-dimethylformamide (10 mL) at 0° C. The resulting mixture was stirredat room temperature for 0.5 hour followed by addition of1-(bromomethyl)-4-fluorobenzene (264 mg, 1.40 mmol). The reactionmixture was stirred at room temperature for another 1.5 hours andquenched by addition of water (20 mL). The resulting solution was thenstirred at room temperature for 5 hours. The pH value of the solutionwas adjusted to 7 with aqueous hydrochloric acid (1 N, 10 mL). Theresulting solution was extracted with ethyl acetate (3×50 mL). Thecombined organic layers were washed with brine, dried over anhydroussodium sulfate, filtered and concentrated under vacuum. The residue waspurified by Prep-HPLC with the following conditions: Column: XBridge C18OBD Prep Column, 100 Å, 5 μm, 19 mm×250 mm; Mobile Phase A: water (0.1%formic acid), Mobile Phase B: ACN; Flow rate: 20 mL/min; Gradient: 40% Bto 60% B over 9 min; UV 254 & 220 nm; Rt: 7 min to afford the titlecompound (100 mg, 33.2%). LC-MS (Method S): m/z=239.2 [M+H]⁺, 1.093 min.

Step 2: Preparation of(S)-4-fluoro-1-(4-fluorobenzyl)-N-(5-methyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepin-3-yl)-1H-pyrazole-3-carboxamide

The crude product obtained using Amide Coupling Procedure C was purifiedby Prep-HPLC with the following conditions: Column: XBridge Prep C18 OBDColumn 19×150 mm 5 m; Mobile Phase A: water (10 mmol/L NH₄HCO₃), MobilePhase B: ACN; Flow rate: 20 mL/min; Gradient: 25% B to 55% B over 7 min;UV 254 & 220 nm; Rt: 6.32 min to afford the title compound. ¹H NMR (400MHz, DMSO-d₆) δ 8.37-8.35 (m, 1H), 8.27 (d, J=8 Hz, 1H), 8.14 (d, J=4.4Hz, 1H), 7.71-7.69 (m, 1H), 7.36-7.32 (m, 3H), 7.25-7.20 (m, 2H), 5.33(s, 2H), 4.87-4.81 (m, 1H), 4.70-4.65 (m, 1H), 4.52-4.48 (m, 1H), 3.35(s, 3H). LC-MS (Method X): m/z=414.2 [M+H]⁺, 2.606 min.

Example 116:(S)—N-(5,6-dihydro-4H-benzo[f]imidazo[1,2-a]azepin-4-yl)-5-(2-fluorophenoxy)pyridazine-3-carboxamide

Step 1: Preparation of 3-chloro-5-(2-fluorophenoxy)pyridazine

2-Fluorophenol (2 g, 17.8 mmol) was added dropwise to a stirring mixtureof 3,5-dichloropyridazine (3.17 g, 21.4 mmol) and cesium carbonate (8.7g, 26.9 mmol) in acetonitrile (40 mL). The reaction mixture was stirredat room temperature for 1 hour under a nitrogen atmosphere. The solidswere removed by filtration and the filtrate was concentrated undervacuum. The residue was purified by column chromatography (petroleumether) to afford the title compound (2.8 g, 70%) as a white solid. LC-MS(Method X): m/z=225.1 [M+H]⁺, 0.919 min.

Step 2: Preparation of ethyl 5-(2-fluorophenoxy)pyridazine-3-carboxylate

1,1′-Bis(diphenylphosphino)ferrocene-palladium(II)dichloridedichloromethane (0.95 g, 1.16 mmol) was added to a mixture of3-chloro-5-(2-fluorophenoxy)pyridazine (2.6 g, 11.6 mmol) and sodiumacetate (1.9 g, 23.2 mmol) in ethanol (125 mL) and N,N-dimethylformamide(25 mL). The reaction mixture was stirred overnight at 90° C. under acarbon monooxide atmosphere (1 MPa). After cooling to room temperature,the reaction mixture was concentrated under vacuum. The residue waspurified by column chromatography (ethyl acetate/petroleum ether, 1/10)to afford the title compound (2.4 g, 79%) as a colorless oil. LC-MS(Method X): m/z=263.1 [M+H]⁺, 0.905 min.

Step 3: Preparation of 5-(2-fluorophenoxy)pyridazine-3-carboxylic acid

Lithium hydroxide (48 mg, 2 mmol) was added to a stirring solution ofethyl 5-(2-fluorophenoxy)pyridazine-3-carboxylate (131 mg, 0.5 mmol) intetrahydrofuran (8 mL) and water (2 mL). The reaction mixture wasstirred for 1 hour at room temperature. After removal of tetrahydrofuranunder reduced pressure, the residue was diluted with water (20 mL). ThepH of the resulting solution was adjusted to 4 with aqueoushydrochloride acid (2 N, 5 mL). The resulting solution was extractedwith ethyl acetate (3×20 mL). The combined organic layers were washedwith brine, dried over anhydrous sodium sulfate, and filtered. Thefiltrate was concentrated under vacuum to afford the title compound (100mg crude) as a white solid. LC-MS (Method R): m/z=235.2 [M+H]⁺, 0.507min.

Step 4: Preparation of(S)—N-(5,6-dihydro-4H-benzo[f]imidazo[1,2-a]azepin-4-yl)-5-(2-fluorophenoxy)pyridazine-3-carboxamide

The crude product obtained using Amide Coupling Procedure C was purifiedby Prep-HPLC with the following conditions: Column: XBridge Prep C18 OBDColumn 19×150 mm 5 μm; Mobile Phase A: water (10 mmol/L NH₄HCO₃), MobilePhase B: ACN, Flow rate: 30 mL/min; Gradient: 45% B to 50% B over 5 min;UV 254 & 220 nm to afford the title compound. ¹H NMR (400 MHz,Methanol-d₄) δ 9.25 (d, J=2.8 Hz, 1H), 7.51-7.32 (m, 10H), 7.08 (d,J=1.2 Hz, 1H), 5.11-5.06 (m, 1H), 2.88-2.81 (m, 1H), 2.80-2.71 (m, 1H),2.66-2.57 (m, 1H), 2.51-2.42 (m, 1H). LC-MS (Method D): m/z=416.1[M+H]⁺, 1.337 min.

Example 117:N-((2R,3S)-2,5-dimethyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepin-3-yl)-4-(2-fluorophenoxy)picolinamide

The crude product obtained using Amide Coupling Procedure C was purifiedby Prep-HPLC with the following conditions: Column: XBridge Shield RP18OBD Column, 5 μm, 19×150 mm; Mobile Phase A: water (0.1% formic acid),Mobile Phase B: ACN; Flow rate: 20 mL/min; Gradient: 35% B to 85% B over7 min; UV 254 & 220 nm; Rt: 6.35 min to afford the title compound. ¹HNMR (400 MHz, DMSO-d₆) δ 8.75 (d, J=6.8 Hz, 1H), 8.64 (d, J=5.6 Hz, 1H),8.36 (dd, J=4.8, 1.6 Hz, 1H), 7.76 (dd, J=8.0, 1.6 Hz, 1H), 7.54-7.39(m, 3H), 7.38-7.33 (m, 3H), 7.27-7.29 (m, 1H), 5.02-4.95 (m, 1H),4.94-4.89 (m, 1H), 3.41 (s, 3H), 1.32 (d, J=6.0 Hz, 3H). LC-MS (MethodQ): m/z=423.0 [M+H]⁺, 2.885 min.

Example 118A & 118B:(R)-5-benzyl-N-(1-methyl-5-oxo-1,4,5,6,7,8-hexahydropyrazolo[4,3-b]azepin-6-yl)-4H-1,2,4-triazole-3-carboxamideand(S)-5-benzyl-N-(1-methyl-5-oxo-1,4,5,6,7,8-hexahydropyrazolo[4,3-b]azepin-6-yl)-4H-1,2,4-triazole-3-carboxamide

Step 1: Preparation of5-benzyl-N-(1-methyl-5-oxo-1,4,5,6,7,8-hexahydropyrazolo[4,3-b]azepin-6-yl)-4H-1,2,4-triazole-3-carboxamide

The crude product obtained using Amide Coupling Procedure C was purifiedby Prep-HPLC with the following conditions: Column: XBridge Prep PhenylOBD Column 19×150 mm 5 μm; Mobile Phase A: water (0.1% formic acid),Mobile Phase B: ACN; Flow rate: 20 mL/min; Gradient: 5% B to 35% B over10 min; UV 254 & 220 nm; Rt: 9 min to afford the title compound (50 mg,38.1%) as a white solid. LC-MS (Method C): m/z=366.2 [M+H]⁺, 1.174 min.

Step 2:(R)-5-benzyl-N-(1-methyl-5-oxo-1,4,5,6,7,8-hexahydropyrazolo[4,3-b]azepin-6-yl)-4H-1,2,4-triazole-3-carboxamide(Example 118A) and(S)-5-benzyl-N-(1-methyl-5-oxo-1,4,5,6,7,8-hexahydropyrazolo[4,3-b]azepin-6-yl)-4H-1,2,4-triazole-3-carboxamide(Example 118B)

The racemate of5-benzyl-N-(1-methyl-5-oxo-1,4,5,6,7,8-hexahydropyrazolo[4,3-b]azepin-6-yl)-4H-1,2,4-triazole-3-carboxamide(50 mg, 0.14 mmol) was separated by Prep-Chiral-HPLC with the followingconditions: Column: CHIRAL ART Cellulose-SB, 2×25 cm, 5 μm; Mobile PhaseA: hexane, Mobile Phase B: EtOH; Flow rate: 20 mL/min; Gradient: 50% Bto 50% B over 12 min; 254/220 nm; Rt1: 8.84 min; Rt2: 10.81 min toafford the title compounds:

Example 118A (first eluting isomer): ¹H NMR (400 MHz, DMSO-d₆) δ 10.00(s, 1H), 8.53 (d, J=5.6 Hz, 1H), 7.41-7.29 (m, 5H), 7.17 (s, 1H),4.41-4.37 (m, 1H), 4.18 (s, 2H), 3.76 (s, 3H), 3.05-3.00 (m, 2H),2.34-2.30 (m, 1H), 2.10-2.05 (m, 1H). LC-MS (Method D): m/z=366.1[M+H]⁺, 1.180 min.

Example 118B (second eluting isomer): ¹H NMR (400 MHz, DMSO-d₆) δ 9.94(s, 1H), 8.46 (d, J=6.0 Hz, 1H), 7.35-7.10 (m, 5H), 7.10 (s, 1H),4.35-4.30 (m, 1H), 4.12 (s, 2H), 3.69 (s, 3H), 3.00-2.92 (m, 2H),2.27-2.23 (m, 1H), 2.04-1.98 (m, 1H). LC-MS (Method D): m/z=366.1[M+H]⁺, 1.177 min.

Example 119A & 119B:5-benzyl-N-((7R,7aR,8aS)-5-methyl-6-oxo-5,6,7,7a,8,8a-hexahydro-cyclopropa[d]pyrazino[2,3-b]azepin-7-yl)-4H-1,2,4-triazole-3-carboxamideand5-benzyl-N-((7S,7aS,8aR)-5-methyl-6-oxo-5,6,7,7a,8,8a-hexahydrocyclopropa[d]pyrazino[2,3-b]azepin-7-yl)-4H-1,2,4-triazole-3-carboxamide

Step 1: Preparation of 3-vinylpyrazin-2-amine

To a solution of 3-bromopyrazin-2-amine (10 g, 57 mmol) inN,N-dimethylformamide (50 mL) was added tributyl(ethenyl)stannane (20 g,63 mmol) and tetrakis(triphenylphosphine)palladium (2.7 g, 2.3 mmol)under a nitrogen atmosphere. The resulting mixture was stirred for 16hours at 80° C., quenched by the addition of water (200 mL) andextracted with dichloromethane (3×200 mL). The combined organic layerswere washed with brine, dried over sodium sulfate, filtered andconcentrated under vacuum. The residue was purified by columnchromatography (methanol/dichloromethane, 3/97) to afford the titlecompound (6.0 g, 86%) as a yellow solid. LC-MS (Method C): m/z=122.1[M+H]⁺, 0.658 min.

Step 2: Preparation of N-(3-vinylpyrazin-2-yl)but-3-enamide

Thionyl chloride (9.3 g, 46.5 mmol) was added to a solution ofbut-3-enoic acid (4.0 g, 46.5 mmol) in dichloromethane (20 mL) dropwise.After stirring for 1 hour at room temperature, the resulting mixture wasadded to a solution of triethylamine (11.8 g, 116.6 mmol) and3-vinylpyrazin-2-amine (4.7 g, 38.7 mmol) in dichloromethane (20 mL).The reaction mixture was stirred for 2 hours at room temperature,quenched by the addition of water (50 mL) and extracted withdichloromethane (3×50 mL). The combined organic layers were washed withbrine, dried over sodium sulfate, filtered and concentrated undervacuum. The residue was purified by column chromatography (ethylacetate/petroleum ether, 3/1) to afford the title compound (5.7 g, 78%)as a yellow oil. LC-MS (Method C): m/z=190.1 [M+H]⁺, 0.881 min.

Step 3: Preparation of (Z)-5H-pyrazino[2,3-b]azepin-6(7H)-one

[1,3-Bis(2,4,6-trimethylphenyl)imidazolidin-2-ylidene]dichloro(phenylmethylidene)ruthenium tricyclohexylphosphine (340 mg, 0.4 mmol) was added to asolution of N-(3-vinylpyrazin-2-yl)but-3-enamide (380 mg, 2 mmol) intoluene (50 mL). The resulting solution was stirred for 16 hours at 80°C. and then concentrated under vacuum. The residue was purified bycolumn chromatography (ethyl acetate/petroleum ether, 5/1) to afford thetitle compound (210 mg, 65%) as a yellow oil. LC-MS (Method C):m/z=162.1 [M+H]⁺, 0.762 min.

Step 4: Preparation of (Z)-5-methyl-5H-pyrazino[2,3-b]azepin-6(7H)-one

Iodomethane (180 mg, 1.3 mmol) was added dropwise to a stirring solutionof (Z)-5H-pyrazino[2,3-b]azepin-6(7H)-one (210 mg, 1.3 mmol) and cesiumcarbonate (1.3 g, 3.9 mmol) in N,N-dimethylformamide (30 mL). Thereaction mixture was stirred for 4 hours at room temperature, dilutedwith water (60 mL) and extracted with ethyl acetate (3×30 mL). Thecombined organic layers were washed with brine, dried over anhydroussodium sulfate, filtered and concentrated under vacuum. The residue waspurified by column chromatography (ethyl acetate/petroleum ether, 4/1)to afford the title compound (200 mg, 88%) as a yellow solid. LC-MS(Method E): m/z=176.1 [M+H]⁺, 0.776 min.

Step 5: Preparation of5-methyl-7,7a,8,8a-tetrahydrocyclopropa[d]pyrazino[2,3-b]azepin-6(5H)-one

To a solution of potassium hydroxide (4 g, 71.4 mmol) in water (6 mL)was added a solution of 1-methyl-1-nitrosourea (2.1 g, 20 mmol) in ether(30 mL) dropwise at 0° C. under a nitrogen atmosphere. The resultingmixture was stirred for 1 hour at 0° C. and then the organic phase wasseparated to provide a solution of diazomethane (30 mL). To a solutionof (Z)-5-methyl-5H-pyrazino[2,3-b]azepin-6(7H)-one (200 mg, 1.1 mmol) intetrahydrofuran (10 mL) was added the solution of diazomethane (30 mL)dropwise, followed by adding a mixture of palladium diacetate (25 mg,0.11 mmol) in tetrahydrofuran (5 mL) dropwise at 0° C. The reactionmixture was stirred overnight at room temperature. The solids wereremoved by filtration and the filtrate was concentrated under vacuum toafford the title compound (110 mg crude) as a yellow oil. LC-MS (MethodE): m/z=190.1 [M+H]⁺, 0.825 min.

Step 6: Preparation oftrans-7-iodo-5-methyl-7,7a,8,8a-tetrahydrocyclopropa[d]pyrazino[2,3-b]azepin-6(5H)-one

To a mixture of5-methyl-7,7a,8,8a-tetrahydrocyclopropa[d]pyrazino[2,3-b]azepin-6(5H)-one(110 mg, 0.6 mmol) in dichloromethane (20 mL) was addedN,N,N′,N′-tetramethylethylene-diamine (210 mg, 1.8 mmol) followed by theaddition of iodotrimethylsilane (360 mg, 1.8 mmol) at 0° C. Afterstirring for 2 hours at 0° C., iodine (230 mg, 0.9 mmol) was added. Thereaction mixture was stirred for 1 hour at 0° C., quenched with aqueoussodium thiosulfate (5%, 40 mL) and extracted with dichloromethane (3×30mL). The combined organic layers were washed with brine, dried overanhydrous sodium sulfate, and filtered. The filtrate was concentratedunder vacuum to afford the title compound (132 mg crude) as a yellowoil. LC-MS (Method E): m/z=316.1 [M+H]⁺, 0.840 min.

Step 7. Preparation ofcis-7-azido-5-methyl-7,7a,8,8a-tetrahydrocyclopropa[d]pyrazino[2,3-b]azepin-6(5H)-one

Sodium azide (39 mg, 0.6 mmol) was added to a mixture oftrans-7-iodo-5-methyl-7,7a,8,8a-tetrahydrocyclopropa[d]pyrazino[2,3-b]azepin-6(5H)-one(132 mg, 0.4 mmol) in N,N-dimethylformamide (10 mL). The resultingmixture was stirred for 16 hours at room temperature, quenched by theaddition of water (30 mL) and extracted with ethyl acetate (3×30 mL).The combined organic layers were washed with brine, dried over sodiumsulfate, and filtered. The filtrate was concentrated under vacuum toafford the title compound (60 mg crude) as a yellow oil. LC-MS (MethodC): m/z=231.1 [M+H]⁺, 1.036 min.

Step 8: Preparation ofcis-7-amino-5-methyl-7,7a,8,8a-tetrahydrocyclopropa[d]pyrazino[2,3-b]azepin-6(5H)-one

Triphenylphosphine (102 mg, 0.39 mmol) was added to a mixture ofcis-7-azido-5-methyl-7,7a,8,8a-tetrahydrocyclopropa[d]pyrazino[2,3-b]azepin-6(5H)-one(60 mg, 0.26 mmol) in tetrahydrofuran (10 mL) and water (1 mL). Theresulting mixture was stirred for 16 hours at room temperature, dilutedwith water (30 mL) and extracted with ethyl acetate (3×30 mL). Thecombined organic layers were washed with brine, dried over anhydroussodium sulfate, filtered and concentrated to dryness under vacuum. Theresidue was purified by column chromatography (methanol/dichloromethane,1/19) to afford the title compound (40 mg, 75%) as a yellow oil. LC-MS(Method E): m/z=205.1 [M+H]⁺, 0.406 min.

Step 9: Preparation of5-benzyl-N-cis-5-methyl-6-oxo-5,6,7,7a,8,8a-hexahydrocyclopropa[d]pyrazino[2,3-b]azepin-7-yl)-4H-1,2,4-triazole-3-carboxamide

N,N-diisopropylethylamine (93 mg, 0.72 mmol) was added to a mixture of5-benzyl-4H-1,2,4-triazole-3-carboxylic acid (51 mg, 0.24 mmol),cis-7-amino-5-methyl-7,7a,8,8a-tetrahydrocyclopropa[d]pyrazino[2,3-b]azepin-6(5H)-one(40 mg, 0.20 mmol), N-(3-dimethylamino-propyl))-N′-ethylcarbodiimidehydrochloride (46 mg, 0.24 mmol) and 1-hydroxybenzotriazole (32 mg, 0.24mmol) in N,N-dimethylformamide (4 mL). The reaction mixture was stirredovernight at room temperature, diluted with water (20 mL) and extractedwith ethyl acetate (3×30 mL). The combined organic layers were washedwith brine, dried over anhydrous sodium sulfate, filtered andconcentrated under vacuum. The residue was purified by Prep-HPLC withthe following conditions: Column: XBridge Prep C18 OBD Column 19×150 mm,5 μm; Mobile Phase A: water (10 mmol/L NH₄HCO₃), Mobile Phase B: ACN;Flow rate: 30 mL/min; Gradient: 25% B to 55% B over 7 min; UV 254 & 220nm to afford the title compound (20 mg, 26%) as a white solid. LC-MS(Method D): m/z=390.2 [M+H]⁺, 1.386 min.

Step 10: Preparation of5-benzyl-N-((7R,7aR,8aS)-5-methyl-6-oxo-5,6,7,7a,8,8a-hexahydro-cyclopropa[d]pyrazino[2,3-b]azepin-7-yl)-4H-1,2,4-triazole-3-carboxamide(Example 119A) and5-benzyl-N-((7S,7aS,8aR)-5-methyl-6-oxo-5,6,7,7a,8,8a-hexahydrocyclopropa[d]-pyrazino[2,3-b]azepin-7-yl)-4H-1,2,4-triazole-3-carboxamide(Example 119B)

The racemate of5-benzyl-N-cis-5-methyl-6-oxo-5,6,7,7a,8,8a-hexahydrocyclopropa[d]-pyrazino[2,3-b]azepin-7-yl)-4H-1,2,4-triazole-3-carboxamide(20 mg, 0.05 mmol) was separated by Prep-Chiral-HPLC with the followingconditions: Column: Chiralpak IA, 2×25 cm, 5 μm; Mobile Phase A: hexane,Mobile Phase B: EtOH; Flow rate: 16 mL/min; Gradient: 55% B to 55% Bover 27 min; 220/254 nm; Rt1: 13.94 min; Rt2: 21.44 min to afford thetitle compounds:

Example 119A (first eluting isomer): ¹H NMR (400 MHz, Methanol-d₄) δ8.44-8.40 (m, 2H), 7.36-7.21 (m, 5H), 4.81 (s, 1H), 4.18 (s, 2H), 3.42(s, 3H), 2.66-2.58 (m, 1H), 2.29-2.18 (m, 1H), 1.57-1.48 (m, 1H),1.36-1.25 (m, 1H). LC-MS (Method D): m/z=390.1 [M+H]⁺, 1.389 min.

Example 119B (second eluting isomer): ¹H NMR (400 MHz, Methanol-d₄) δ8.46-8.38 (m, 2H), 7.39-7.21 (m, 5H), 4.81 (s, 1H), 4.18 (s, 2H), 3.42(s, 3H), 2.66-2.58 (m, 1H), 2.30-2.22 (m, 1H), 1.57-1.50 (m, 1H),1.35-1.26 (m, 1H). LC-MS (Method D): m/z=390.2 [M+H]⁺, 1.384 min.

Example 120A and 120B:5-benzyl-N-((1aS,2S,8bR)-4-methyl-3-oxo-1,1a,2,3,4,8b-hexahydrocyclopropa[d]pyrido[2,3-b]azepin-2-yl)-1,3,4-thiadiazole-2-carboxamideand5-benzyl-N-((1aR,2R,8bS)-4-methyl-3-oxo-1,1a,2,3,4,8b-hexahydrocyclopropa-[d]pyrido[2,3-b]azepin-2-yl)-1,3,4-thiadiazole-2-carboxamide

Step 1: Preparation of5-benzyl-N-(cis-4-methyl-3-oxo-1,1a,2,3,4,8b-hexahydrocyclopropa[d]pyrido[2,3-b]azepin-2-yl)-1,3,4-thiadiazole-2-carboxamide

The crude product obtained using Amide Coupling Procedure C was purifiedby Prep-HPLC with the following conditions: Column: XBridge Prep C18 OBDColumn 19×150 mm 5 μm; Mobile Phase A: water (10 mmol/L NH₄HCO₃), MobilePhase B: ACN; Flow rate: 20 mL/min; Gradient: 25% B to 55% B over 7 min;UV 254 & 220 nm; Rt: 6.32 min to afford the title compound (20 mg,32.9%) as a white solid. LC-MS (Method I): m/z=406.2 [M+H]⁺, 1.001 min.

Step 2: Preparation of5-benzyl-N-((1aS,2S,8bR)-4-methyl-3-oxo-1,1a,2,3,4,8b-hexahydrocy-clopropa[d]pyrido[2,3-b]azepin-2-yl)-1,3,4-thiadiazole-2-carboxamide(Example 120A) and5-benzyl-N-((1aR,2R,8bS)-4-methyl-3-oxo-1,1a,2,3,4,8b-hexahydrocyclopropa-[d]pyrido[2,3-b]azepin-2-yl)-1,3,4-thiadiazole-2-carboxamide(Example 120B)

The racemate of5-benzyl-N-(cis-4-methyl-3-oxo-1,1a,2,3,4,8b-hexahydrocyclopropa-[d]-pyrido[2,3-b]azepin-2-yl)-1,3,4-thiadiazole-2-carboxamide(20 mg, 0.049 mmol) was separated by Prep-chiral-separation withfollowing conditions: Column: Lux Cellulose-4, 0.46×5 cm, 3 μm; MobilePhase A: hexane; Mobile Phase B: EtOH; Flow rate: 1.0 mL/min; Gradient:50% B to 50% B over 8 min; UV 254 & 220 nm; Rt1: 4.09 min; Rt2: 6.43 minto afford the title compounds:

Example 120A (first eluting isomer): ¹H NMR (400 MHz, Methanol-d₄) δ8.38 (dd, J=4.8, 2.0 Hz, 1H), 7.94 (dd, J=7.6, 2.0 Hz, 1H), 7.41-7.26(m, 6H), 4.64 (s, 1H), 4.53 (s, 2H), 3.41 (s, 3H), 2.33-2.25 (m, 1H),2.15-2.06 (m, 1H), 1.34-1.28 (m, 1H), 1.21-1.12 (m, 1H). LC-MS (MethodD): m/z=406.1 [M+H]⁺, 1.703 min.

Example 120B (second eluting isomer): ¹H NMR (400 MHz, Methanol-d₄) δ8.36 (dd, J=4.8, 2.0 Hz, 1H), 7.91 (dd, J=7.6, 2.0 Hz, 1H), 7.38-7.24(m, 6H), 4.62 (s, 1H), 4.50 (s, 2H), 3.38 (s, 3H), 2.29-2.24 (m, 1H),2.12-2.06 (m, 1H), 1.32-1.26 (m, 1H), 1.22-1.14 (m, 1H). LC-MS (MethodV): m/z=406.1 [M+H]⁺, 2.915 min.

Example 121A & 121B:(R)-4-(2,4-difluorophenoxy)-N-(9-methyl-8-oxo-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]azepin-7-yl)picolinamideand(S)-4-(2,4-difluorophenoxy)-N-(9-methyl-8-oxo-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]azepin-7-yl)picolinamide

Step 1: Preparation of methyl 4-(2,4-difluorophenoxy)picolinate

To a sealed tube were added methyl 4-chloropicolinate (1 g, 5.85 mmol),2,4-difluorophenol (1.14 g, 8.77 mmol), cesium carbonate (5.7 g, 17.5mmol), copper powder (0.38 g, 5.94 mmol) and N,N-dimethylformamide (10mL). The resulting mixture was heated at 100° C. by microwaveirradiation and stirred for 3 hours, diluted with water (20 mL) andextracted with ethyl acetate (3×50 mL). The combined organic layers werewashed with brine, dried over anhydrous sodium sulfate, and filtered.The filtrate was concentrated under vacuum to afford the title compound(0.5 g crude) as a white solid. LC-MS (Method I): m/z=265.9 [M+H]⁺,0.926 min.

Step 2: Preparation of 4-(2,4-difluorophenoxy)picolinic acid

Lithium hydroxide (260 mg, 10.8 mmol) was added to a stirring mixture ofmethyl 4-phenoxypicolinate (500 mg, 1.89 mmol) in tetrahydrofuran (10mL) and water (5 mL). The resulting solution was stirred overnight atroom temperature. After removal of tetrahydrofuran under reducedpressure, the pH of the aqueous solution was adjusted to 6 with aqueoushydrochloric acid (1 N, 10 mL). The resulting mixture was extracted withethyl acetate (3×30 mL). The combined organic layers were washed withbrine, dried over anhydrous sodium sulfate, and filtered. The filtratewas concentrated under vacuum to afford the title compound (200 mgcrude) as a white solid, which was used directly in the next stepwithout further purification. LC-MS (Method X): m/z=252.2 [M+H]⁺, 0.639min.

Step 3: Preparation of4-(2,4-difluorophenoxy)-N-(9-methyl-8-oxo-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]azepin-7-yl)picolinamide

The crude product obtained using Amide Coupling Procedure C was purifiedby Prep-HPLC with the following conditions: Column: XBridge Shield RP18OBD Column, 19×150 mm 5 μm; Mobile Phase A: water (10 mmol/L NH₄HCO₃),Mobile Phase B: ACN; Flow rate: 20 mL/min; Gradient: 40% B to 70% B over7 min; 254 & 220 nm; Rt: 5.590 min to afford the title compound (80 mg,40.1%) as a white solid. LC-MS (Method R): m/z=425.3 [M+H]⁺, 1.442 min.

Step 4: Preparation of(R)-4-(2,4-difluorophenoxy)-N-(9-methyl-8-oxo-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]azepin-7-yl)picolinamide(Example 121A) and(S)-4-(2,4-difluorophenoxy)-N-(9-methyl-8-oxo-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]azepin-7-yl)picolinamide(Example 121B)

The racemate of4-(2,4-difluorophenoxy)-N-(9-methyl-8-oxo-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]azepin-7-yl)picolinamide(80 mg, 0.19 mmol) was separated by Prep-Chiral-HPLC with the followingconditions: Column: Chiralpak ID-2, 2×25 cm, 5 μm; Mobile Phase A:hexane, Mobile Phase B: EtOH; Flow rate: 15 mL/min; Gradient: 55% B to55% B over 23 min; UV 220 & 254 nm; Rt1: 14.83 min; Rt2: 18.87 min toafford the title compounds:

Example 121A (first eluting isomer): ¹H NMR (400 MHz, DMSO-d₆) δ 8.88(d, J=8.0 Hz, 1H), 8.60 (d, J=5.6 Hz, 1H), 8.44-8.43 (m, 1H), 7.84-7.81(m, 1H), 7.65-7.48 (m, 2H), 7.36-7.22 (m, 4H), 4.36-4.29 (m, 1H), 3.36(s, 3H), 2.81-2.70 (m, 2H), 2.50-2.44 (m, 1H), 2.35-2.21 (m, 1H). LC-MS(Method T): m/z=425.25 [M+H]⁺, 1.432 min.

Example 121B (second eluting isomer): ¹H NMR (400 MHz, DMSO-d₆) δ 8.88(d, J=7.6 Hz, 1H), 8.60 (d, J=5.6 Hz, 1H), 8.44-8.43 (m, 1H), 7.84-7.81(m, 1H), 7.61-7.50 (m, 2H), 7.34-7.24 (m, 4H), 4.34-4.31 (m, 1H), 3.36(s, 3H), 2.77-2.73 (m, 2H), 2.51-2.50 (m, 1H), 2.31-2.21 (m, 1H). LC-MS(Method X): m/z=425.25 [M+H]⁺, 1.437 min.

Example 122:3-benzyl-N-((2R,3S)-2,5-dimethyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepin-3-yl)isoxazole-5-carboxamide

Step 1: Preparation of (E)-2-phenylacetaldehyde oxime

Sodium hydroxide (1.2 g, 30.0 mmol) was added to a mixture of2-phenylacetaldehyde (1.2 g, 10.0 mmol) and hydroxylamine hydrochloride(1.4 g, 20.3 mmol) in ethanol (40 mL) and water (20 mL). The resultingmixture was stirred at room temperature for 5 hours, diluted with water(50 mL) and extracted with dichloromethane (3×80 mL). The combinedorganic layers were washed with brine, dried over anhydrous sodiumsulfate, filtered and concentrated under vacuum. The residue waspurified by column chromatography (methanol/dichloromethane, 1/20) toafford the title compound (400 mg, 29.6%) as a white solid. LC-MS(Method E): m/z=136.0 [M+H]⁺, 0.371 min.

Step 2: Preparation of ethyl 3-benzylisoxazole-5-carboxylate

Ethyl propiolate (2.7 g, 27.5 mmol) was added to a mixture of(E)-2-phenylacetaldehyde oxime (400 mg, 2.9 mmol) and chromium oxide(2.5 g, 29.7 mmol) in acetonitrile (50 mL). The reaction mixture wasstirred at 80° C. for 5 hours. Solids were removed by filtration and thefiltrate was evaporated under vacuum. The residue was purified by columnchromatography (ethyl acetate/petroleum ether, 1/2) to afford the titlecompound (200 mg, 40%) as a yellow solid. LC-MS (Method C): m/z=232.0[M+H]⁺, 1.200 min.

Step 3: Preparation of3-benzyl-N-((2R,3S)-2,5-dimethyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepin-3-yl)isoxazole-5-carboxamide

The crude product obtained using the procedure described in Example 54was purified by Prep-HPLC with the following conditions: Column: XBridgeC18 OBD Prep Column, 100 Å, 19×250 mm 5 μm; Mobile Phase A: water (10mmol/L NH₄HCO₃), Mobile Phase B: ACN; Flow rate: 20 mL/min; Gradient:35% B to 55% B over 7 min; UV 254 & 220 nm; Rt: 7 min to afford thetitle compound. ¹H NMR (400 MHz, DMSO-d₆) δ 8.73 (d, J=7.6 Hz, 1H),8.34-8.33 (m, 1H), 7.71-7.69 (m, 1H), 7.36-7.24 (m, 6H), 7.18 (s, 1H),5.03-4.99 (m, 1H), 4.84-4.78 (m, 1H), 4.06 (s, 2H), 3.40 (s, 3H), 1.37(d, J=6.4 Hz, 3H). LC-MS (Method D): m/z=393.1 [M+H]⁺, 1.787 min.

Example 123:(S)-5-benzyl-N-(4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepin-3-yl)thiazole-2-carboxamide

The crude product obtained using the procedure described in Example 54was purified by Prep-HPLC with the following conditions: Column: XBridgeC18 OBD Prep Column, 100 Å, 5 μm, 19 mm×250 mm; Mobile Phase A: water(10 mmol/L NH₄HCO₃), Mobile Phase B: ACN; Flow rate: 20 mL/min;Gradient: 20% B to 40% B over 7 min; UV 254 & 220 nm; Rt: 7 min toafford the title compound. ¹H NMR (300 MHz, DMSO-d₆) δ 10.56 (s, 1H),8.92 (d, J=7.9 Hz, 1H), 8.15 (dd, J=4.7, 1.5 Hz, 1H), 7.88 (s, 1H), 7.56(dd, J=8.0, 1.5 Hz, 1H), 7.41-7.12 (m, 6H), 4.88-4.74 (m, 1H), 4.62-4.41(m, 2H), 4.28 (s, 2H). LC-MS (Method O): m/z=381.0 [M+H]⁺, 1.290 min.

Example124:5-benzyl-N-((2R,3S)-2,5-dimethyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepin-3-yl)thiazole-2-carboxamide

The crude product obtained using Amide Coupling Procedure C was purifiedby Prep-HPLC with the following conditions: Column: XBridge C18 OBD PrepColumn, 19×150 mm, 5 μm; Mobile Phase A: water (10 mmol/L NH₄HCO₃),Mobile Phase B: ACN; Flow rate: 20 mL/min; Gradient: 40% B to 60% B over7 min; UV 254 & 220 nm to afford the title compound (18.8 mg, 9%) as awhite semi-solid. ¹H NMR (400 MHz, Methanol-d₄) δ 8.36-8.30 (m, 1H),7.76-7.65 (m, 2H), 7.37-7.22 (m, 6H), 5.04-4.96 (m, 2H), 4.26 (s, 2H),3.50 (s, 3H), 1.42 (d, J=6.0 Hz, 3H). LC-MS (Method D): m/z=409.2[M+H]⁺, 1.638 min.

Example 125A & 125B:(R)-5-benzyl-N-(9′-methyl-8′-oxo-6′,7′,8′,9′-tetrahydrospiro[cyclopropane-1,5′-pyrido[2,3-b]azepin]-7′-yl)-4H-1,2,4-triazole-3-carboxamide(125A) and(S)-5-benzyl-N-(9′-methyl-8′-oxo-6′,7′,8′,9′-tetrahydrospiro[cyclopropane-1,5′-pyrido[2,3-b]azepin]-7′-yl)-4H-1,2,4-triazole-3-carboxamide(125B)

Step 1: Preparation of dimethyl 2-(2-nitropyridin-3-yl)malonate

Dimethyl malonate (14 g, 105.6 mmol) was added dropwise to a stirringmixture of 3-fluoro-2-nitropyridine (10 g, 70.4 mmol) and potassiumcarbonate (19.5 g, 140.8 mmol) in N,N-dimethylformamide (25 mL) at roomtemperature. The reaction mixture was stirred overnight at 70° C.,quenched by the addition of water (50 mL) and extracted with ethylacetate (3×50 mL). The combined organic layers were washed with brine,dried over anhydrous sodium sulfate, filtered and concentrated undervacuum. The residue was purified by column chromatography (ethylacetate/petroleum ether, 1/4) to afford the title compound (18 g, 89.8%)as a brown oil. LC-MS (Method R): m/z=255.1 [M+H]⁺, 0.762 min.

Step 2: Preparation of methyl 2-(2-nitropyridin-3-yl)acetate

A solution of lithium chloride (8 g, 189 mmol) in water (10 mL) wasadded to a mixture of dimethyl 2-(2-nitropyridin-3-yl)malonate (16 g, 63mmol) in dimethyl sulfoxide (50 mL). The reaction mixture was stirred at100° C. overnight, quenched by the addition of water (50 mL) andextracted with ethyl acetate (3×50 mL). The combined organic layers werewashed with brine, dried over anhydrous sodium sulfate, filtered andconcentrated under vacuum to afford the title compound (12 g crude) as abrown oil. LC-MS (Method R): m/z=197.1 [M+H]⁺, 0.673 min.

Step 3: Preparation of methyl1-(2-nitropyridin-3-yl)cyclopropanecarboxylate

1,2-Dibromoethane (17 g, 91.8 mmol) was added dropwise to a stirringmixture of 3-fluoro-2-nitropyridine (12 g, 61.2 mmol) and potassiumcarbonate (25.3 g, 183.6 mmol) in N,N-dimethylformamide (25 mL) at roomtemperature. The reaction mixture was stirred overnight at 70° C.,quenched by the addition of water (50 mL) and extracted with ethylacetate (3×50 mL). The combined organic layers were washed with brine,dried over anhydrous sodium sulfate, filtered and concentrated undervacuum. The residue was purified by column chromatography (ethylacetate/petroleum ether, 1/3) to afford the title compound (5 g, 36.8%)as a red oil. LC-MS (Method R): m/z=223.1 [M+H]⁺, 0.802 min.

Step 4: Preparation of (1-(2-nitropyridin-3-yl)cyclopropyl)methanol

A solution of diisobutylaluminium hydride in toluene (1 M, 45 mL, 45mmol) was added dropwise to a stirring solution of methyl1-(2-nitropyridin-3-yl)cyclopropanecarboxylate (5 g, 22.5 mmol) intoluene (50 mL) at −78° C. The reaction mixture was stirred at −78° C.for 2 hours, quenched by the addition of water (2 mL) and concentratedunder vacuum. The residue was purified by column chromatography (ethylacetate/petroleum ether, 1/3) to afford the title compound (3 g, 68.6%)as a yellow solid. LC-MS (Method C): m/z=195.1 [M+H]⁺, 0.975 min.

Step 5: Preparation of 1-(2-nitropyridin-3-yl)cyclopropanecarbaldehyde

Dess-Martin periodinane (13 g, 30.9 mmol) was added to a stirringsolution of (1-(2-nitropyridin-3-yl)cyclopropyl)methanol (3 g, 15.5mmol) in dichloromethane (100 mL). The reaction mixture was stirred at0° C. for 2 hours, quenched by the addition of water (50 mL) andextracted with dichloromethane (3×50 mL). The combined organic layerswere washed with brine, dried over sodium sulfate, filtered andconcentrated under vacuum. The residue was purified by columnchromatography (ethyl acetate/petroleum ether, 1/3) to afford the titlecompound (2.5 g, 84.2%) as a yellow oil. LC-MS (Method C): m/z=193.0[M+H]⁺, 1.002 min.

Step 6: Preparation of (Z)-methyl2-(tert-butoxycarbonylamino)-3-(1-(2-nitropyridin-3-yl)cyclopropyl)acrylate

1,8-Diazabicyclo[5.4.0]undec-7-ene (4 g, 26 mmol) was added to astirring solution of methyl2-{[(tert-butoxy)carbonyl]amino}-2-(dimethoxyphosphoryl)acetate (7.7 g,26 mmol) in tetrahydrofuran (50 mL). The reaction mixture was stirred at70° C. for 1 hour followed by the addition of a solution of1-(2-nitropyridin-3-yl)cyclopropanecarbaldehyde (2.5 g, 13 mmol) intetrahydrofuran (50 mL). Then the reaction mixture was stirred overnightat 70° C., quenched by the addition of water (50 mL) and extracted withdichloromethane (3×100 mL). The combined organic layers were washed withbrine, dried over anhydrous sodium sulfate, filtered and concentratedunder vacuum. The residue was purified by column chromatography (ethylacetate/petroleum ether, 1/4) to afford the title compound (3 g, 63.5%)as a yellow solid. LC-MS (Method E): m/z=364.0 [M+H]⁺, 0.860 min.

Step 7: Preparation of methyl3-(1-(2-aminopyridin-3-yl)cyclopropyl)-2-(tert-butoxycarbonyl-amino)propanoate

(Z)-methyl2-(tert-butoxycarbonylamino)-3-(1-(2-nitropyridin-3-yl)cyclopropyl)acrylate(3 g, 8.26 mmol) in methanol (50 mL) was hydrogenated in the presence ofpalladium on carbon (10%, 0.3 g) under a hydrogen atmosphere (2-3 atm).The reaction mixture was stirred overnight at room temperature under ahydrogen atmosphere. The solids were removed by filtration and thefiltrate was concentrated under high vacuum to afford the title compound(2.5 g crude) as a white solid. LC-MS (Method C): m/z=336.1 [M+H]⁺,0.926 min.

Step 8: Preparation of3-(1-(2-aminopyridin-3-yl)cyclopropyl)-2-(tert-butoxycarbonylamino)propanoic acid

Lithium hydroxide (358 mg, 14.9 mmol) was added to a solution of methyl3-(1-(2-aminopyridin-3-yl)cyclopropyl)-2-(tert-butoxycarbonylamino)propanoate(2.5 g, 7.46 mmol) in tetrahydrofuran (15 mL) and water (5 mL). Thereaction mixture was stirred at room temperature overnight andconcentrated under vacuum. The residue was diluted with water (20 mL)and adjusted to pH=7 with aqueous hydrochloride acid (1 N, 10 mL) andextracted with ethyl acetate (3×10 mL). The combined organic layers werewashed with brine, dried over anhydrous sodium sulfate and concentratedunder vacuum to afford the title compound (1 g crude) as a white solid.LC-MS (Method R): m/z=322.1 [M+H]⁺, 0.580 min.

Step 9: Preparation of tert-butyl(8′-oxo-6′,7′,8′,9′-tetrahydrospiro[cyclopropane-1,5′-pyrido[2,3-b]azepin]-7′-yl)carbamate

N,N-diisopropylethylamine (1.2 g, 9.34 mmol) was added to a mixture of3-(1-(2-aminopyridin-3-yl)cyclopropyl)-2-(tert-butoxycarbonylamino)propanoicacid (1 g, 3.11 mmol),2-(7-aza-1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluroniumhexafluorophosphate (1.59 g, 3.73 mmol) in N,N-dimethylformamide (20mL). The reaction mixture was stirred for 2 hours at room temperature,quenched by the addition of water (20 mL) and extracted with ethylacetate (3×50 mL). The combined organic layers were washed with brine,dried over anhydrous sodium sulfate, filtered and concentrated undervacuum. The residue was purified by column chromatography (ethylacetate/petroleum ether, 1/3) to afford the title compound (500 mg, 53%)as a yellow solid. LC-MS (Method R): m/z=304.0 [M+H]⁺, 0.842 min.

Step 10: Preparation of tert-butyl(9′-methyl-8′-oxo-6′,7′,8′,9′-tetrahydrospiro[cyclopropane-1,5′-pyrido[2,3-b]azepin]-7′-yl)carbamate

Iodomethane (52 mg, 0.36 mmol) was added dropwise to a stirring solutionoftert-butyl(8′-oxo-6′,7′,8′,9′-tetrahydrospiro[cyclopropane-1,5′-pyrido[2,3-b]azepin]-7′-yl)carbamate(110 mg, 0.36 mmol) and cesium carbonate (119 mg, 0.36 mmol) inN,N-dimethylformamide (5 mL) at 0° C. The reaction mixture was stirred 2hours at room temperature, quenched by the addition of water (50 mL) andextracted with ethyl acetate (3×50 mL). The combined organic layers werewashed with brine, dried over anhydrous sodium sulfate, filtered andconcentrated under vacuum. The residue was purified by columnchromatography (ethyl acetate/petroleum ether, 1/4) to afford the titlecompound (110 mg, 95.6%) as a white solid. LC-MS (Method C): m/z=218.1[M+H-100]⁺, 1.613 min.

Step 11: Preparation of7′-amino-9′-methyl-6′,7′-dihydrospiro[cyclopropane-1,5′-pyrido[2,3-b]azepin]-8′(9′H)-onehydrochloride

A solution of hydrogen chloride in 1,4-dioxane (4 M, 10 mL, 40 mmol) wasadded to a solution of tert-butyl(9′-methyl-8′-oxo-6′,7′,8′,9′-tetrahydrospiro[cyclopropane-1,5′-pyrido[2,3-b]azepin]-7′-yl)carbamate(110 mg, 0.34 mmol) in 1,4-dioxane (4 mL). The reaction mixture wasstirred for 2 hours at room temperature and concentrated under highvacuum to afford the title compound (80 mg crude) as a white solid.LC-MS (Method C): m/z=218.1 [M+H]⁺, 0.777 min.

Step 12: Preparation of5-benzyl-N-(9′-methyl-8′-oxo-6′,7′,8′,9′-tetrahydrospiro-[cyclopropane-1,5′-pyrido[2,3-b]azepin]-7′-yl)-4H-1,2,4-triazole-3-carboxamide

N,N-diisopropylethylamine (107 mg, 0.828 mmol) was added to a mixture of5-benzyl-4H-1,2,4-triazole-3-carboxylic acid (62 mg, 0.304 mmol),7′-amino-9′-methyl-6′,7′-dihydrospiro[cyclopropane-1,5′-pyrido[2,3-b]azepin]-8′(9′H)-onehydrochloride (60 mg, 0.276 mmol),N-(3-dimethylaminopropyl))-N′-ethylcarbodiimide hydrochloride (69 mg,0.359 mmol) and 1-hydroxybenzotriazole (49 mg, 0.359 mmol) inN,N-dimethylformamide (4 mL). The reaction mixture was stirred overnightat room temperature, diluted with water (20 mL) and extracted with ethylacetate (3×50 mL). The combined organic layers were washed with brine,dried over anhydrous sodium sulfate, filtered and concentrated undervacuum. The residue was purified by Prep-HPLC with the followingconditions: Column: X Bridge Prep C18 OBD Column 19×150 mm, 5 μm; MobilePhase A: water (10 mmol/L NH₄HCO₃), Mobile Phase B: ACN; Flow rate: 30mL/min; Gradient: 25% B to 55% B over 7 min; UV 254 & 220 nm to affordthe title compound. LC-MS (Method D): m/z=403.1 [M+H]⁺, 1.460 min.

Step 13: Preparation of(R)-5-benzyl-N-(9′-methyl-8′-oxo-6′,7′,8′,9′-tetrahydrospiro-[cyclopropane-1,5′-pyrido[2,3-b]azepin]-7′-yl)-4H-1,2,4-triazole-3-carboxamide(First Eluting Isomer) and(S)-5-benzyl-N-(9′-methy-8′-oxo-6′,7′,8′,9′-tetrahydrospiro[cyclopropane-1,5′-pyrido[2,3-b]azepin]-7′-yl)-4H-1,2,4-triazole-3-carboxamide(Second Eluting Isomer)

The racemate of5-benzyl-N-(9′-methyl-8′-oxo-6′,7′,8′,9′-tetrahydrospiro-[cyclopropane-1,5′-pyrido[2,3-b]azepin]-7′-yl)-4H-1,2,4-triazole-3-carboxamide(60 mg, 0.149 mmol) was separated by Prep-Chiral-HPLC with the followingconditions: Column: Chiralpak ID-2, 2×25 cm, 5 μm; Mobile Phase A:hexane/DCM (4.5/1), Mobile Phase B: EtOH; Flow rate: 17 mL/min;Gradient: 50% B to 50% B over 22 min; UV 254 & 220 nm; RT 1: 11.72 min;RT 2: 18.02 min to afford the title compounds:

Example 125A (first eluting isomer): ¹H NMR (300 MHz, DMSO-d₆) δ 14.27(s, 1H), 8.41 (dd, J=4.8, 1.8 Hz, 2H), 7.75 (dd, J=7.6, 1.8 Hz, 1H),7.34-7.18 (m, 6H), 4.42-4.33 (m, 1H), 4.09 (s, 2H), 3.31 (s, 3H),2.73-2.63 (m, 1H), 1.73-1.62 (m, 1H), 1.09-1.05 (m, 1H), 0.70 (d, J=5.4Hz, 2H), 0.36 (d, J=10.0 Hz, 1H). LC-MS (Method D): m/z=403.1 [M+H]⁺,1.661 min.

Example 125B (second eluting isomer): ¹H NMR (300 MHz, DMSO-d₆) δ 14.27(s, 1H), 8.41 (dd, J=4.8, 1.8 Hz, 2H), 7.75 (dd, J=7.6, 1.8 Hz, 1H),7.35-7.18 (m, 6H), 4.40-4.33 (m, 1H), 4.09 (s, 2H), 3.30 (s, 3H), 2.69(t, J=10.6 Hz, 1H), 1.68 (t, J=12.3 Hz, 1H), 1.07 (d, J=10.0 Hz, 1H),0.70 (d, J=5.5 Hz, 2H), 0.36 (d, J=9.9 Hz, 1H). LC-MS (Method D):m/z=403.1 [M+H]⁺, 1.673 min.

Example 126:(S)-5-benzyl-4-fluoro-N-(5-methyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepin-3-yl)thiazole-2-carboxamide

Step 1: Preparation of methyl 4-fluoro-5-methylthiazole-2-carboxylate

1-Chloromethyl-4-fluoro-1,4-diazoniabicyclo[2.2.2]octanebis(tetrafluoroborate) (7.0 g, 19.8 mmol) was added to a mixture ofmethyl 4-fluoro-5-methylthiazole-2-carboxylate (1.6 g, 10.2 mmol) inacetonitrile (50 mL) under a nitrogen atmosphere. The reaction mixturewas heated to reflux and stirred overnight, diluted with water (50 mL)and extracted with ethyl acetate (3×40 mL). The combined organic layerswere dried over anhydrous sodium sulfate, filtered and concentratedunder vacuum. The residue was purified by column chromatography (ethylacetate/petroleum ether, 1/3) to afford the title compound (600 mg,33.7%) as a white solid. LC-MS (Method C): m/z=176.1 [M+H]⁺, 1.240 min.

Step 2: Preparation of methyl5-(bromomethyl)-4-fluorothiazole-2-carboxylate

Benzoyl peroxide (10 mg, 0.04 mmol) was added to a mixture ofN-bromosuccinimide (650 mg, 3.6 mmol) and methyl4-fluoro-5-methylthiazole-2-carboxylate (600 mg, 3.4 mmol) in carbontetrachloride (20 mL). The reaction mixture was stirred overnight at 75°C. Solids were removed by filtration. The filtrate was diluted withwater (20 mL) and extracted with ethyl acetate (3×20 mL). The combinedorganic layers were washed with saturated sodium bicarbonate (20 mL) andbrine, dried over anhydrous sodium sulfate, filtered and concentratedunder vacuum. The residue was purified by column chromatography (ethylacetate/petroleum ether, 1/2) to afford the title compound (600 mg,68.9%) as a yellow solid. LC-MS (Method F): m/z=254 [M+H]⁺, 1.490 min.

Step 3: Preparation of methyl 5-benzyl-4-fluorothiazole-2-carboxylate

Tetrakis(triphenylphosphine)palladium (147 mg, 0.13 mmol) was added to amixture of methyl 5-(bromomethyl)-4-fluorothiazole-2-carboxylate (582mg, 2.3 mmol), phenylboronic acid (402 mg, 3.3 mmol) and sodiumcarbonate (1 g, 9.4 mmol) in toluene (20 mL) and ethanol (10 mL) under anitrogen atmosphere. The reaction mixture was stirred at 80° C.overnight, quenched by the addition of water (20 mL) and extracted withethyl acetate (3×40 mL). The combined organic layers were washed withbrine, dried over anhydrous sodium sulfate, filtered and concentratedunder vacuum. The residue was purified by column chromatography (ethylacetate/petroleum ether, 1/2) to afford the title compound (400 mg,66.6%) as a yellow solid. LC-MS (Method C): m/z=252.2 [M+H]⁺, 1.971 min.

Step 4:(S)-5-benzyl-4-fluoro-N-(5-methyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepin-3-yl)thiazole-2-carboxamide

The crude product obtained using the procedure described in Example 54was purified by Prep-HPLC with the following conditions: Column: XBridgePrep C18 OBD Column, 19×150 mm, 5 μm; Mobile phase A: water (10 mmol/LNH₄HCO₃), Mobile phase B: ACN; 40% ACN up to 70% B over 7 min; UV 254 &220 nm to afford the title compound. ¹H NMR (400 MHz, DMSO-d₆) δ 9.14(d, J=7.6 Hz, 1H), 8.36 (dd, J=4.8, 1.6 Hz, 1H), 7.70 (dd, J=8.0, 1.6Hz, 1H), 7.39-7.21 (m, 6H), 4.88-4.71 (m, 2H), 4.51 (t, J=5.6 Hz, 1H),4.17 (s, 2H), 3.34 (s, 3H). LC-MS (Method V): m/z=413.00 [M+H]⁺, 2.480min.

Example 127:1-(4-Cyanobenzyl)-N-((2R,3S)-2,5-dimethyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepin-3-yl)-4-fluoro-1H-pyrazole-3-carboxamide

Step 1: Preparation of1-(4-cyanobenzyl)-4-fluoro-1H-pyrazole-3-carboxylic acid

Sodium hydride (60%, 144 mg, 6 mmol) was added to a stirring mixture ofethyl 4-fluoro-1H-pyrazole-3-carboxylate (474 mg, 3 mmol) inN,N-dimethylformamide (20 mL). The resulting mixture was stirred for 2hours at room temperature, followed by the addition of4-(bromomethyl)benzonitrile (585 mg, 3 mmol). The resulting mixture wasstirred for 2 hours at room temperature. After the addition of water (20mL), the reaction mixture was stirred overnight at room temperature, thepH was adjusted to 6 with aqueous hydrochloric acid (1 N, 10 mL) andextracted with ethyl acetate (3×50 mL). The combined organic layers werewashed with brine, dried over anhydrous sodium sulfate, filtered andconcentrated under vacuum. The residue was purified by Prep-HPLC withthe following conditions: Column: XBridge C18 OBD Prep Column, 100 Å, 5μm, 19 mm×250 mm; Mobile Phase A: Water (0.1% formic acid), Mobile PhaseB: ACN; Flow rate: 20 mL/min; Gradient: 30% B to 50% B over 7 min; UV254 & 220 nm; Rt: 7 min to afford the title compound (250 mg, 34%) as awhite solid. LC-MS (Method C): m/z=246.1 [M+H]⁺, 0.969 min.

Step 2: Preparation of1-(4-cyanobenzyl)-N-((2R,3S)-2,5-dimethyl-4-oxo-2,3,4,5tetrahydropyrido[3,2-b][1,4]oxazepin-3-yl)-4-fluoro-1H-pyrazole-3-carboxamide

The crude product obtained using Amide Coupling Procedure C was purifiedby Prep-HPLC with the following conditions: Column: XBridge C18 OBD PrepColumn, 100 Å, 5 μm, 19 mm×250 mm; Mobile Phase A: Water (0.1% formicacid), Mobile Phase B: ACN; Flow rate: 20 mL/min; Gradient: 25% B to 48%B over 12 min; UV 254 & 220 nm; Rt: 7 min to afford the title compound.¹H NMR (400 MHz, DMSO-d₆) δ 8.35 (dd, J=4.8, 1.6 Hz, 1H), 8.20 (d, J=4.4Hz, 1H), 7.88-7.85 (m, 2H), 7.75 (dd, J=8.0, 1.6 Hz, 1H), 7.61 (d, J=6.4Hz, 1H), 7.44-7.41 (m, 2H), 7.36 (dd, J=8.0, 4.8 Hz, 1H), 5.50 (s, 2H),4.99-4.88 (m, 2H), 3.39 (s, 3H), 1.31 (d, J=6.4 Hz, 3H). LC-MS (MethodX): m/z=435.2 [M+H]⁺, 1.355 min.

Example 128:1-(3-Cyanobenzyl)-N-((2R,3S)-2,5-dimethyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepin-3-yl)-4-fluoro-1H-pyrazole-3-carboxamide

Step 1: Preparation of1-(3-cyanobenzyl)-4-fluoro-1H-pyrazole-3-carboxylic acid

Sodium hydride (60%, 144 mg, 6 mmol) was added to a stirring mixture ofethyl 4-fluoro-1H-pyrazole-3-carboxylate (474 mg, 3 mmol) inN,N-dimethylformamide (20 mL) at 0° C. The resulting mixture was stirredfor 2 hours at room temperature, followed by addition of4-(bromomethyl)benzonitrile (585 mg, 3 mmol). The reaction mixture wasstirred for another 2 hours at room temperature. After addition of water(20 mL), the resulting mixture was stirred overnight at roomtemperature. The pH value of the solution was adjusted to 6 with aqueoushydrochloric acid (1 N, 10 mL). The resulting mixture was extracted withethyl acetate (3×50 mL). The combined organic layers were washed withbrine, dried over anhydrous sodium sulfate, filtered and concentratedunder vacuum. The residue was purified by Prep-HPLC with the followingconditions: Column: XBridge Prep C18 OBD Column 19×150 mm, 5 μm; MobilePhase A: water (0.1% formic acid), Mobile Phase B: ACN; Flow rate: 20mL/min; Gradient: 20% B to 50% B over 7 min; UV 254 & 220 nm; Rt: 6 minto afford the title compound (230 mg, 31%) as a white solid. LC-MS(Method C): m/z=246.1 [M+H]⁺, 1.236 min.

Step 2: Preparation of1-(3-cyanobenzyl)-N-((2R,3S)-2,5-dimethyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepin-3-yl)-4-fluoro-1H-pyrazole-3-carboxamide

The crude product obtained using Amide Coupling Procedure C was purifiedby Prep-HPLC with the following conditions: Column: XBridge C18 OBD PrepColumn, 100 Å, 5 μm, 19 mm×250 mm; Mobile Phase A: water (0.1% formicacid), Mobile Phase B: ACN; Flow rate: 20 mL/min; Gradient: 25% B to 48%B over 12 min; UV 254 & 220 nm; Rt: 7 min to afford the title compound.¹H NMR (400 MHz, DMSO-d₆) δ 8.36 (dd, J=4.8, 1.6 Hz, 1H), 8.19 (d, J=4.4Hz, 1H), 7.86-7.79 (m, 2H), 7.75 (dd, J=8.0, 1.6 Hz, 1H), 7.62-7.60 (m,3H), 7.36 (dd, J=8.0, 4.4 Hz, 1H), 5.45 (s, 2H), 4.99-4.88 (m, 2H), 3.40(s, 3H), 1.32 (d, J=6.0 Hz, 3H). LC-MS (Method D): m/z=435.1 [M+H]⁺,1.659 min.

Example 129A and 129B:(S)-5-Benzyl-N-(2,4-dimethyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-4H-1,2,4-triazole-3-carboxamideand(R)-5-Benzyl-N-(2,4-dimethyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-4H-1,2,4-triazole-3-carboxamide

Step 1: Preparation of methyl4-(3-methyl-5-nitro-1H-pyrazol-1-yl)butanoate

Sodium hydride (60%, 2.5 g, 63 mmol) was added to a mixture of3-methyl-5-nitro-1H-pyrazole (8 g, 63 mmol) in tetrahydrofuran (80 mL)at 0° C. The resulting mixture was stirred for 0.5 hour at 0° C.followed by the addition of methyl 4-bromobutanoate (11.2 g, 63 mmol).The reaction mixture was stirred for 1 hour at 0° C., quenched by theaddition of water (40 mL) and extracted with ethyl acetate (3×60 mL).The combined organic layers were washed with brine, dried over sodiumsulfate, filtered and concentrated under vacuum. The residue waspurified by column chromatography (ethyl acetate/petroleum ether, 1/10)to afford the title compound (2.2 g, 15%) as a colorless oil. LC-MS(Method C): m/z=228.1 [M+H]⁺, 1.180 min.

Step 2: Preparation of methyl4-(5-amino-3-methyl-1H-pyrazol-1-yl)butanoate

A mixture of methyl 4-(3-methyl-5-nitro-1H-pyrazol-1-yl)butanoate (2.2g, 9.7 mmol) in methanol (50 mL) was hydrogenated in the presence ofpalladium on carbon (10%, 0.2 g) under a hydrogen atmosphere (2-3 atm).After stirring for 2 hours at room temperature under hydrogenatmosphere, the reaction mixture was filtered through Celite. Thefiltrate was concentrated under vacuum to afford the title compound (1.8g, 94%) as a yellow solid. LC-MS (Method C): m/z=198.1 [M+H]⁺, 0.733min.

Step 3: Preparation of2-methyl-7,8-dihydro-4H-pyrazolo[1,5-a][1,3]diazepin-5(6H)-one

The crude product obtained using the procedure described in Example 54was purified by column chromatography (methanol/dichloromethane, 1/10)to afford the title compound (1.0 g, 66%) as a yellow solid. LC-MS(Method C): m/z=166.1 [M+H]⁺, 0.755 min.

Step 4: Preparation of2,4-dimethyl-7,8-dihydro-4H-pyrazolo[1,5-a][1,3]diazepin-5(6H)-one

Iodomethane (0.74 g, 5.4 mmol) was added dropwise to a stirring mixtureof 2-methyl-7,8-dihydro-4H-pyrazolo[1,5-a][1,3]diazepin-5(6H)-one (0.90g, 5.4 mmol) and cesium carbonate (5.28 g, 16.2 mmol) inN,N-dimethylformamide (15 mL). The reaction mixture was stirred for 3hours at room temperature, diluted with water (20 mL) and extracted withethyl acetate (3×50 mL). The combined organic layers were washed withbrine, dried over anhydrous sodium sulfate, filtered and concentratedunder vacuum. The residue was purified by column chromatography(methanol/dichloromethane, 1/20) to afford the title compound (0.72 g,74%) as a yellow solid. LC-MS (Method C): m/z=180.1 [M+H]⁺, 0.865 min.

Step 5: Preparation of6-iodo-2,4-dimethyl-7,8-dihydro-4H-pyrazolo[1,5-a][1,3]diazepin-5(6H)-one

N¹,N¹,N²,N²-tetramethylethane-1,2-diamine (1.2 g, 12.0 mmol) was addedto a stirring mixture of2,4-dimethyl-7,8-dihydro-4H-pyrazolo[1,5-a][1,3]diazepin-5(6H)-one (720mg, 4.0 mmol) in dichloromethane (10 mL) at 0° C. followed by additionof iodotrimethylsilane (2.4 g, 12.0 mmol) dropwise over 20 min. Thereaction mixture was stirred for 1 hour at 0° C. After addition ofiodine (2.0 g, 8.0 mmol), the reaction mixture was stirred for another 1hour at 0° C. Then the mixture was quenched by the addition of aqueoussodium thiosulfate (5%, 20 mL), stirred for another 15 minutes andextracted with ethyl acetate (3×50 mL). The combined organic layers werewashed with brine, dried over anhydrous sodium sulfate, filtered andconcentrated under vacuum. The residue was purified by columnchromatography (dichloromethane) to afford the title compound (500 mg,41%) as a yellow solid. LC-MS (Method C): m/z=306.0 [M+H]⁺, 1.033 min.

Step 6: Preparation of6-azido-2,4-dimethyl-7,8-dihydro-4H-pyrazolo[1,5-a][1,3]diazepin-5(6H)-one

Sodium azide (137 mg, 2.10 mmol) was added to a mixture of6-iodo-2,4-dimethyl-7,8-dihydro-4H-pyrazolo[1,5-a][1,3]diazepin-5(6H)-one(500 mg, 1.64 mmol) in N,N-dimethylformamide (10 mL). The resultingmixture was stirred for 2 hours at room temperature, quenched by theaddition of water (40 mL) and extracted with ethyl acetate (3×50 mL).The combined organic layers were washed with brine, dried over sodiumsulfate, filtered and concentrated under vacuum to afford the titlecompound (280 mg crude) as a yellow oil. LC-MS (Method S): m/z=221.3[M+H]⁺, 0.763 min.

Step 7. Preparation of6-amino-2,4-dimethyl-7,8-dihydro-4H-pyrazolo[1,5-a][1,3]diazepin-5(6H)-one

Triphenylphosphine (734 mg, 2.80 mmol) was added to a stirring mixtureof6-azido-2,4-dimethyl-7,8-dihydro-4H-pyrazolo[1,5-a][1,3]diazepin-5(6H)-onein tetrahydrofuran (10 mL) and water (2 mL). The reaction mixture wasstirred overnight at room temperature, diluted with water (20 mL) andextracted with ethyl acetate (3×50 mL). The combined organic layers werewashed with brine, dried over anhydrous sodium sulfate, filtered andconcentrated under vacuum. The residue was purified by columnchromatography (methanol/dichloromethane, 1/10) to afford the titlecompound (200 mg, 62%) as a yellow oil. LC-MS (Method I): m/z=195.0[M+H]⁺, 0.263 min.

Step 8: Preparation of5-benzyl-N-(2,4-dimethyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-4H-1,2,4-triazole-3-carboxamide

N,N-diisopropylethylamine (140 mg, 1.13 mmol) was added to a mixture of5-benzyl-4H-1,2,4-triazole-3-carboxylic acid (73 mg, 0.36 mmol),6-amino-2,4-dimethyl-7,8-dihydro-4H-pyrazolo[1,5-a][1,3]diazepin-5(6H)-one(70 mg, 0.36 mmol), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimidehydrochloride (77 mg, 0.39 mmol) and 1-hydroxybenzotriazole (65 mg, 0.39mmol) in N,N-dimethylformamide (2 mL). The reaction mixture was stirredovernight at room temperature, diluted with water (10 mL) and extractedwith ethyl acetate (3×20 mL). The combined organic layers were washedwith brine, dried over anhydrous sodium sulfate, filtered andconcentrated under vacuum. The residue was purified by Prep-HPLC withthe following conditions: Column: XBridge Prep C18 OBD Column, 5 μm,19×150 mm; Mobile Phase A: water (0.1% formic acid), Mobile Phase B:ACN; Flow rate: 20 mL/min; Gradient: 15% B to 45% B over 7 min; UV 254 &220 nm; Rt: 6 min to afford the title compound (50 mg, 36%) as a whitesolid. LC-MS (Method Y): m/z=380.2 [M+H]⁺, 0.750 min.

Step 9: Preparation of(S)-5-benzyl-N-(2,4-dimethyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-4H-1,2,4-triazole-3-carboxamide (129A) and(R)-5-benzyl-N-(2,4-dimethyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-4H-1,2,4-triazole-3-carboxamide(129B)

The racemate of5-benzyl-N-(2,4-dimethyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-4H-1,2,4-triazole-3-carboxamide was separatedby Prep-Chiral-HPLC with the following conditions: Column: Chiralpak IC,2×25 cm, 5 μm; Mobile Phase A: hexane, Mobile Phase B: EtOH; Flow rate:20 mL/min; Gradient: 50% B to 50% B over 22 min; UV 254 & 220 nm; Rt 1:10.04 min; Rt 2: 18.12 min to afford the title compounds:

Example 129A (first eluting isomer): ¹H NMR (300 MHz, DMSO-d₆) δ 14.31(s, 1H), 8.55 (s, 1H), 7.40-7.18 (m, 5H), 6.13 (s, 1H), 4.41-4.20 (m,2H), 4.20-4.02 (m, 3H), 3.23 (s, 3H), 2.65-2.26 (m, 2H), 2.18 (s, 3H).LC-MS (Method D): m/z=380.2 [M+H]⁺, 1.298 min.

Example 129B (second eluting isomer): ¹H NMR (300 MHz, DMSO-d₆) δ 14.30(s, 1H), 8.46 (s, 1H), 7.38-7.20 (m, 5H), 6.13 (s, 1H), 4.41-4.20 (m,2H), 4.20-4.02 (m, 3H), 3.23 (s, 3H), 2.61-2.37 (m, 2H), 2.17 (s, 3H).LC-MS (Method D): m/z=380.2 [M+H]⁺, 1.300 min.

Example 130:(S)-1-(3-Cyano-5-fluorobenzyl)-4-fluoro-N-(5-methyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepin-3-yl)-1H-pyrazole-3-carboxamide

Step 1: Preparation of 3-fluoro-5-(hydroxymethyl)benzonitrile

Sodium borohydride (1.0 g, 6.71 mmol) was added to a stirring mixture of3-fluoro-5-formylbenzonitrile (306 mg, 8.05 mmol) in ethanol (10 mL) andtetrahydrofuran (10 mL) at 0° C. under nitrogen atmosphere. Afterstirring at 0° C. for 1 hour, the reaction mixture was concentratedunder vacuum, diluted with water (50 mL) and extracted with ethylacetate (3×50 mL). The combined organic layers were washed with brine,dried over anhydrous sodium sulfate, filtered and concentrated undervacuum to afford the title compound (980 mg crude) as a yellow solid.LC-MS (Method T): m/z=152.3 [M+H]⁺, 0.671 min.

Step 2: Preparation of 3-(bromomethyl)-5-fluorobenzonitrile

Tribromophosphine (2.9 g, 10.7 mmol) was added to a stirring mixture of3-fluoro-5-(hydroxymethyl)benzonitrile (0.8 g, 5.30 mmol) indichloromethane (10 mL). After stirring overnight at room temperature,the reaction mixture was concentrated under vacuum to afford the titlecompound (0.8 g crude) as a yellow solid, which was used directly in thenext step without further purification.

Step 3: Preparation of(S)-1-(3-cyano-5-fluorobenzyl)-4-fluoro-N-(5-methyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepin-3-yl)-1H-pyrazole-3-carboxamide

Potassium carbonate (55 mg, 0.40 mmol) was added to a stirring mixtureof(S)-4-fluoro-N-(5-methyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepin-3-yl)-1H-pyrazole-3-carboxamide(40 mg, 0.13 mmol) and 3-(bromomethyl)-5-fluorobenzonitrile (34 mg, 0.16mmol) in N,N-dimethylformamide (2 mL). After stirring at roomtemperature for 2 hours, the reaction mixture was diluted with water (20mL) and extracted with ethyl acetate (3×20 mL). The combined organiclayers were washed with brine, dried over anhydrous sodium sulfate,filtered and concentrated under vacuum. The residue was purified byPrep-HPLC with the following conditions: Column: XBridge Prep C18 OBDColumn, 5 μm, 19×150 mm; Mobile Phase A: water (10 mmol/L NH₄HCO₃),Mobile Phase B: ACN; Flow rate: 30 mL/min; Gradient: 35% B to 65% B over5 min; UV 254 & 220 nm; Rt: 3.75 min to afford the title compound. ¹HNMR (400 MHz, DMSO-d₆) δ 8.37 (dd, J=4.8, 1.6 Hz, 1H), 8.28 (d, J=8.0Hz, 1H), 8.18 (d, J=4.4 Hz, 1H), 7.90-7.86 (m, 1H), 7.71 (dd, J=7.6, 1.2Hz, 1H), 7.66 (s, 1H), 7.56-7.52 (m, 1H), 7.36-7.32 (m, 1H), 5.44 (s,2H), 4.89-4.81 (m, 1H), 4.70-4.64 (m, 1H), 4.54-4.49 (m, 1H), 3.36 (s,3H). LC-MS (Method X): m/z=439.2 [M+H]⁺, 1.291 min.

Example 131A and 131B:(S)-5-Benzyl-N-(3,4-dimethyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-4H-1,2,4-triazole-3-carboxamideand(R)-5-Benzyl-N-(3,4-dimethyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-4H-1,2,4-triazole-3-carboxamide

Step 1: Preparation of methyl4-(4-methyl-5-nitro-1H-pyrazol-1-yl)butanoate

Diisopropyl azodicarboxylate (3.4 g, 16.9 mmol) was slowly added to astirring mixture of methyl 4-hydroxybutanoate (2 g, 16.9 mmol),4-methyl-5-nitro-1H-pyrazole (1 g, 7.8 mmol) and triphenylphosphine(4.44 g, 16.9 mmol) in tetrahydrofuran (40 mL) at 0° C. under nitrogenatmosphere. After stirring overnight at room temperature, the reactionmixture was quenched by the addition of water (100 mL) and extractedwith ethyl acetate (3×100 mL). The combined organic layers were washedwith brine, dried over sodium sulfate, filtered and concentrated undervacuum. The residue was purified by column chromatography (ethylacetate/petroleum ether, 1/10) to afford the title compound (1.0 g, 56%)as a colorless oil. LC-MS (Method C): m/z=228.1 [M+H]⁺, 1.130 min.

Step 2: Preparation of methyl4-(5-amino-4-methyl-1H-pyrazol-1-yl)butanoate

A solution of methyl 4-(4-methyl-5-nitro-1H-pyrazol-1-yl)butanoate (1.0g, 4.4 mmol) in methanol (30 mL) was hydrogenated in the presence ofpalladium on carbon (10%, 0.1 g) under a hydrogen atmosphere (2-3 atm).After stirring for 2 hours at room temperature under hydrogenatmosphere, the reaction mixture was filtered through Celite. Thefiltrate was concentrated under vacuum to afford the title compound(0.85 mg, 97%) as a yellow solid. LC-MS (Method I): m/z=197.9 [M+H]⁺,1.013 min.

Step 3: Preparation of3-methyl-7,8-dihydro-4H-pyrazolo[,5-a][1,3]diazepin-5(6H)-one

The crude product obtained using the procedure described in Example 54was purified by column chromatography (methanol/dichloromethane, 1/10)to afford the title compound (600 mg, 84%) as a yellow solid. LC-MS(Method C): m/z=166.1 [M+H]⁺, 0.782 min.

Step 4: Preparation of3,4-dimethyl-7,8-dihydro-4H-pyrazolo[1,5-a][1,3]diazepin-5(6H)-one

Iodomethane (511 mg, 3.6 mmol) was added to a stirring mixture of3-methyl-7,8-dihydro-4H-pyrazolo[1,5-a][1,3]diazepin-5(6H)-one (600 mg,3.6 mmol) and cesium carbonate (3.52 g, 10.8 mmol) inN,N-dimethylformamide (15 mL). The reaction mixture was stirred for 3hours at room temperature, diluted with water (50 mL) and extracted withethyl acetate (3×50 mL). The combined organic layers were washed withbrine, dried over anhydrous sodium sulfate, filtered and concentratedunder vacuum. The residue was purified by column chromatography(methanol/dichloromethane, 1/20) to afford the title compound (480 mg,78%) as a yellow solid. LC-MS (Method C): m/z=180.1 [M+H]⁺, 0.876 min.

Step 5: Preparation of6-iodo-3,4-dimethyl-7,8-dihydro-4H-pyrazolo[1,5-a][1,3]diazepin-5(6H)-one

N¹,N¹,N²,N²-tetramethylethane-1,2-diamine (0.82 mg, 8.02 mmol) was addedto a stirring mixture of3,4-dimethyl-7,8-dihydro-4H-pyrazolo[1,5-a][1,3]diazepin-5(6H)-one (0.48mg, 2.67 mmol) in dichloromethane (10 mL) at 0° C. followed by theaddition of iodotrimethylsilane (1.6 g, 8.01 mmol). After stirring for 1hour at 0° C., iodine (1.36 g, 5.35 mmol) was added. The reactionmixture was stirred for another 1 hour at 0° C. and quenched by theaddition of aqueous sodium thiosulfate (5%, 20 mL). The resultingmixture was stirred for another 15 minutes and extracted with ethylacetate (3×50 mL). The combined organic layers were washed with brine,dried over anhydrous sodium sulfate, filtered and concentrated undervacuum. The residue was purified by column chromatography(dichloromethane) to afford the title compound (0.427 g, 52%) as ayellow solid. LC-MS (Method I): m/z=305.9 [M+H]⁺, 0.756 min.

Step 6: Preparation of6-azido-3,4-dimethyl-7,8-dihydro-4H-pyrazolo[1,5-a][1,3]diazepin-5(6H)-one

Sodium azide (137 mg, 2.1 mmol) was added to a stirring mixture of6-iodo-3,4-dimethyl-7,8-dihydro-4H-pyrazolo[1,5-a][1,3]diazepin-5(6H)-one(427 mg, 1.39 mmol) in N,N-dimethylformamide (10 mL). The reactionmixture was stirred for 2 hours at room temperature, quenched with water(40 mL) and extracted with ethyl acetate (3×50 mL). The combined organiclayers were washed with brine, dried over anhydrous sodium sulfate,filtered and concentrated under vacuum to afford the title compound (400mg crude) as a yellow oil. LC-MS (Method C): m/z=220.7 [M+H]⁺, 1.383min.

Step 7: Preparation of6-amino-3,4-dimethyl-7,8-dihydro-4H-pyrazolo[1,5-a][1,3]diazepin-5(6H)-one

Triphenylphosphine (734 mg, 2.80 mmol) was added to a stirring mixtureof6-azido-3,4-dimethyl-7,8-dihydro-4H-pyrazolo[1,5-a][1,3]diazepin-5(6H)-one(400 mg, 1.80 mmol) in tetrahydrofuran (10 mL) and water (2 mL). Afterstirring overnight at room temperature, the reaction mixture was dilutedwith water (10 mL) and extracted with ethyl acetate (3×20 mL). Thecombined organic layers were washed with brine, dried over anhydroussodium sulfate, filtered and concentrated under vacuum. The residue waspurified by column chromatography (methanol/dichloromethane, 1/10) toafford the title compound (232 mg, 86%) as a yellow oil. LC-MS (MethodC): m/z=194.7 [M+H]⁺, 0.378 min.

Step 8: Preparation of5-benzyl-N-(3,4-dimethyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-4H-1,2,4-triazole-3-carboxamide

N,N-diisopropylethylamine (140 mg, 1.13 mmol) was added to a mixture of5-benzyl-4H-1,2,4-triazole-3-carboxylic acid (73 mg, 0.36 mmol),6-amino-3,4-dimethyl-7,8-dihydro-4H-pyrazolo[1,5-a][1,3]diazepin-5(6H)-one(70 mg, 0.36 mmol), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimidehydrochloride (77 mg, 0.39 mmol) and 1-hydroxybenzotriazole (65 mg, 0.39mmol) in N,N-dimethylformamide (2 mL). After stirring overnight at roomtemperature, the reaction mixture was diluted with water (20 mL) andextracted with ethyl acetate (3×40 mL). The combined organic layers werewashed with brine, dried over anhydrous sodium sulfate, filtered andconcentrated under vacuum. The residue was purified by Prep-HPLC withthe following conditions: Column: XBridge C18 OBD Prep Column 100 Å, 10μm, 19 mm×250 mm; Mobile Phase A: water (0.05% formic acid), MobilePhase B: ACN; Flow rate: 20 mL/min; Gradient: 22% B to 43% B over 7 min;UV 254 & 220 nm; Rt: 7 min to afford the title compound (50 mg, 36%) asa white solid. LC-MS (Method T): m/z=380.3 [M+H]⁺, 1.041 min.

Step 9: Preparation of(S)-5-benzyl-N-(3,4-dimethyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-4H-1,2,4-triazole-3-carboxamide (131A) and(R)-5-benzyl-N-(3,4-dimethyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-4H-1,2,4-triazole-3-carboxamide(131B)

The racemate of5-benzyl-N-(3,4-dimethyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl)-4H-1,2,4-triazole-3-carboxamide(50 mg, 0.13 mmol) was separated by Prep-Chiral-HPLC with the followingconditions: Column: Chiralpak IF, 2×25 cm, 5 μm; Mobile Phase A: hexane,Mobile Phase B: EtOH; Flow rate: 17 mL/min; Gradient: 40% B to 40% Bover 24 min; UV 254 & 220 nm; Rt 1: 7.35 min; Rt 2: 8.28 min to affordthe title compounds:

Example 131A (first eluting isomer): ¹H NMR (300 MHz, DMSO-d₆) δ 14.31(s, 1H), 8.34 (d, J=7.7 Hz, 1H), 7.40-7.18 (m, 6H), 4.36-4.09 (m, 5H),3.22 (s, 3H), 2.61-2.23 (m, 2H), 2.02 (s, 3H). LC-MS (Method D):m/z=380.2 [M+H]⁺, 1.312 min.

Example 131B (second eluting isomer): ¹H NMR (300 MHz, DMSO-d₆) δ 14.31(s, 1H), 8.34 (d, J=7.6 Hz, 1H), 7.38-7.20 (m, 6H), 4.30-4.14 (m, 5H),3.22 (s, 3H), 2.60-2.27 (m, 2H), 2.02 (s, 3H). LC-MS (Method D):m/z=380.2 [M+H]⁺, 1.312 min.

Example 132:1-Benzyl-4-chloro-N-((2R,3S)-2,5-dimethyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepin-3-yl)-1H-pyrazole-3-carboxamide

Step 1: Preparation of ethyl 4-chloro-1H-pyrazole-3-carboxylate

1-Chloropyrrolidine-2,5-dione (5.75 g, 42.9 mmol) was added to astirring mixture of ethyl 1H-pyrazole-3-carboxylate (5.00 g, 35.7 mmol)in N,N-dimethylformamide (40 mL). The reaction mixture was stirredovernight at room temperature and diluted with water (100 mL). Thesolids were removed by filtration and the filtrate was concentratedunder vacuum to afford the title compound (6.0 g crude) as a yellow oil.LC-MS (Method S): m/z=175.2 [M+H]⁺, 0.695 min.

Step 2: Preparation of ethyl 1-benzyl-4-chloro-1H-pyrazole-3-carboxylate

Potassium carbonate (7.1 g, 51.4 mmol) was added to a stirring mixtureof (ethyl 4-chloro-1H-pyrazole-3-carboxylate (3.0 g, 17.1 mmol) and(bromomethyl)benzene (3.6 g, 21.1 mmol) in N,N-dimethylformamide (10mL). The reaction mixture was stirred at room temperature overnight,diluted with water (30 mL) and extracted with ethyl acetate (3×50 mL).The combined organic layers were washed with brine, dried over anhydroussodium sulfate, filtered and concentrated to dryness under vacuum. Theresidue was purified by column chromatography (ethyl acetate/petroleumether, 1/3) to afford the title compound (2.0 g, 44%) as a colorlessoil. LC-MS (Method S): m/z=265.2 [M+H]⁺, 1.040 min.

Step 3: Preparation of1-benzyl-4-chloro-N-((2R,3S)-2,5-dimethyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepin-3-yl)-1H-pyrazole-3-carboxamide

The crude product obtained using the procedure described in Example 54was purified by Prep-HPLC with the following conditions: Column: XBridgeC18 OBD Prep Column, 100 Å, 5 μm, 19 mm×250 mm; Mobile Phase A: water(10 mmol/L NH₄HCO₃), Mobile Phase B: ACN; Flow rate: 20 mL/min;Gradient: 40% B to 65% B over 7 min; UV 254 & 220 nm; Rt: 7 min toafford the title compound. ¹H NMR (400 MHz, DMSO-d₆) δ 8.36 (dd, J=4.8,1.6 Hz, 1H), 8.26 (s, 1H), 7.76-7.71 (m, 2H), 7.42-7.29 (m, 6H), 5.42(s, 2H), 4.99-4.88 (m, 2H), 3.40 (s, 3H), 1.32 (d, J=6.0 Hz, 3H). LC-MS(Method T): m/z=426.2 [M+H]⁺, 1.518 min.

Example 133:(S)-4-Fluoro-1-(2-fluorobenzyl)-N-(5-methyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepin-3-yl)-1H-pyrazole-3-carboxamide

Potassium carbonate (34 mg, 0.25 mmol) was added to a mixture of(S)-4-fluoro-N-(5-methyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepin-3-yl)-1H-pyrazole-3-carboxamide(25 mg, 0.08 mmol) and 1-(bromomethyl)-2-fluorobenzene (19 mg, 0.10mmol) in N,N-dimethylformamide (2 mL). After stirring at roomtemperature for 3 hours, the reaction mixture was diluted with water (2mL) and extracted with ethyl acetate (3×20 mL). The combined organiclayers were washed with brine, dried over anhydrous sodium sulfate,filtered and concentrated to dryness under vacuum. The residue waspurified by Prep-HPLC with the following conditions: Column: XBridgePrep C18 OBD Column, 5 μm, 19×150 mm; Mobile Phase A: water (10 mmol/LNH₄HCO₃), Mobile Phase B: ACN; Flow rate: 30 mL/min; Gradient: 35% B to65% B over 5 min; UV 254 & 220 nm; Rt: 3.75 min to afford the titlecompound. ¹H NMR (400 MHz, DMSO-d₆) δ 8.37 (dd, J=4.8, 1.6 Hz, 1H), 8.24(d, J=7.6 Hz, 1H), 8.12 (d, J=4.4 Hz, 1H), 7.71 (dd, J=8.0, 1.6 Hz, 1H),7.46-7.40 (m, 1H), 7.35-7.21 (m, 4H), 5.43 (s, 2H), 4.88-4.80 (m, 1H),4.70-4.64 (m, 1H), 4.53-4.48 (m, 1H), 3.35 (s, 3H). LC-MS (Method T):m/z=414.2 [M+H]⁺, 1.346 min.

Example 134:5-Benzyl-N-((2R,3S)-2,5-dimethyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepin-3-yl)-1,3,4-oxadiazole-2-carboxamide

The crude product obtained using the procedure described in Example 54was purified by Prep-HPLC with the following conditions: Column: XBridgeShield RP18 OBD Column, 5 μm, 19×150 mm; Mobile Phase A: water (10mmol/L NH₄HCO₃), Mobile Phase B: ACN; Flow rate: 20 mL/min; Gradient:15% B to 60% B over 15 min; UV 254 & 220 nm; Rt: 14.5 min to afford thetitle compound (13.3 mg, 17%) as a white solid. ¹H NMR (400 MHz,Methanol-d₄) δ 8.33-8.31 (m, 1H), 7.71-7.67 (m, 1H), 7.37-7.28 (m, 6H),5.07-4.97 (m, 2H), 4.34 (s, 2H), 3.50 (s, 3H), 1.44 (d, J=6.0 Hz, 3H).LC-MS (Method J): m/z=394.15 [M+H]⁺, 2.483 min.

Example 135:(S)-4-Fluoro-1-(3-fluorobenzyl)-N-(5-methyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepin-3-yl)-1H-pyrazole-3-carboxamide

Step 1: Preparation of 4-fluoro-1H-pyrazole-3-carboxylic acid

Sodium hydroxide (253 mg, 6.33 mmol) was added to a mixture of ethyl4-fluoro-1H-pyrazole-3-carboxylate (500 mg, 3.16 mmol) in methanol (10mL) and water (4 mL). The resulting solution was heated to 40° C. andstirred overnight. After removal of methanol under reduced pressure, theresulting solution was adjusted to pH=6 with aqueous hydrochloric acid(1 N, 20 mL) and extracted with ethyl acetate (3×50 mL). The combinedorganic layers were washed with brine, dried over anhydrous sodiumsulfate, and filtered. The filtrate was concentrated under vacuum toafford the title compound (400 mg, 97.2%) as a white solide. LC-MS(Method T): m/z=131.4 [M+H]⁺, 0.567 min.

Step 2: Preparation of(S)-4-fluoro-N-(5-methyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepin-3-yl)-1H-pyrazole-3-carboxamide

N,N-diisopropylethylamine (993 mg, 7.70 mmol) was added to a mixture of(S)-3-amino-5-methyl-2,3-dihydropyrido[3,2-b][1,4]oxazepin-4(5H)-onehydrochloride (354 mg, 1.54 mmol), 4-fluoro-1H-pyrazole-3-carboxylicacid (200 mg, 1.54 mmol), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimidehydrochloride (355 mg, 1.85 mmol) and 1-hydroxybenzotriazole (250 mg,1.85 mmol) in N,N-dimethylformamide (10 mL). After stirring overnight atroom temperature, the reaction mixture was diluted with water (30 mL)and extracted with ethyl acetate (3×50 mL). The combined organic layerswere washed with brine, dried over anhydrous sodium sulfate, filteredand concentrated under vacuum. The residue was purified by Prep-TLC(ethyl acetate) to afford the title compound (200 mg, 42.6%) as a whitesolid. LC-MS (Method T): m/z=306.3 [M+H]⁺, 0.696 min.

Step 3: Preparation of(S)-4-fluoro-1-(3-fluorobenzyl)-N-(5-methyl-4-oxo-2,3,4,5-tetrahydropyrido-[3,2-b][1,4]oxazepin-3-yl)-1H-pyrazole-3-carboxamide

Potassium carbonate (68 mg, 0.49 mmol) was added to a mixture of(S)-4-fluoro-N-(5-methyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepin-3-yl)-1H-pyrazole-3-carboxamide(50 mg, 0.16 mmol) and 1-(bromomethyl)-3-fluorobenzene (38 mg, 0.20mmol) in N,N-dimethylformamide (5 mL). After stirring at roomtemperature for 3 hours, the reaction mixture was diluted with water (5mL) and extracted with ethyl acetate (3×30 mL). The combined organiclayers were washed with brine, dried over anhydrous sodium sulfate,filtered and concentrated under vacuum. The residue was purified byPrep-HPLC with the following conditions: Column: XBridge Shield RP18 OBDColumn, 5 μm, 19×150 mm; Mobile Phase A: water (10 mmol/L NH₄HCO₃),Mobile Phase B: ACN; Flow rate: 20 mL/min; Gradient: 35% B to 78% B over7 min; UV 254 & 220 nm; Rt: 6.5 min to afford the title compound. ¹H NMR(400 MHz, DMSO-d₆) δ 8.36 (d, J=4.0 Hz, 1H), 8.27 (d, J=8.0 Hz, 1H),8.16 (d, J=4.4 Hz, 1H), 7.70 (d, J=7.6 Hz, 1H), 7.49-7.38 (m, 1H),7.38-7.28 (m, 1H), 7.22-6.98 (m, 3H), 5.38 (s, 2H), 4.92-4.78 (m, 1H),4.78-4.61 (m, 1H), 4.61-4.41 (m, 1H), 3.36 (s, 3H). LC-MS (Method T):m/z=414.2 [M+H]⁺, 1.347 min.

Example 136:1-Benzyl-N-((2R,3S)-2,5-dimethyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide

Step 1: Preparation of methyl 1-benzyl-1H-1,2,4-triazole-3-carboxylate

Sodium hydride (60%, 192 mg, 8 mmol) was added to a stirring mixture ofmethyl 1H-1,2,4-triazole-3-carboxylate (508 mg, 4 mmol) inN,N-dimethylformamide (10 mL). The resulting mixture was stirred at roomtemperature for 2 hours followed by the addition of (bromomethyl)benzene(680 mg, 4 mmol) under a nitrogen atmosphere. After stirring for another2 hours, the reaction mixture was quenched by the addition of water (20mL) and extracted with ethyl acetate (3×50 mL). The combined organiclayers were washed with brine, dried over anhydrous sodium sulfate,filtered and concentrated under vacuum. The residue was purified bycolumn chromatography (ethyl acetate/petroleum ether, 1/2) to afford thetitle compound (400 mg, 46%) as a white solid. LC-MS (Method E):m/z=217.9 [M+H]⁺, 0.661 min.

Step 2: Preparation of 1-benzyl-1H-1,2,4-triazole-3-carboxylic acid

Lithium hydroxide (48 mg, 2 mmol) was added to a stirring mixture ofmethyl 1-benzyl-1H-1,2,4-triazole-3-carboxylate (108 mg, 0.5 mmol) intetrahydrofuran (3 mL) and water (1 mL). After stirring at 0° C. for 2hours, the pH of the reaction mixture was adjusted to 6 with aqueoushydrochloric acid (1 N, 10 mL) and extracted with ethyl acetate (3×20mL). The combined organic layers were washed with brine, dried overanhydrous sodium sulfate, and filtered. The filtrate was concentratedunder vacuum to afford the title compound (80 mg, 79%) as a white solid.LC-MS (Method E): m/z=203.9 [M+H]⁺, 0.560 min.

Step 3: Preparation of1-benzyl-N-((2R,3S)-2,5-dimethyl-4-oxo-2,3,4,5-tetrahydro-pyrido[3,2-b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide

The crude product obtained using Amide Coupling Procedure C was purifiedby Prep-HPLC with the following conditions: Column: XBridge C18 OBD PrepColumn, 100 Å, 5 μm, 19 mm×250 mm; Mobile Phase A: water (10 mmol/LNH₄HCO₃), Mobile Phase B: ACN; Flow rate: 20 mL/min; Gradient: 25% B to75% B over 7 min; UV 254 & 220 nm; Rt: 6.3 min to afford the titlecompound (31.5 mg, 40%) as a white solid. ¹H NMR (400 MHz, DMSO-d₆) δ8.86 (s, 1H), 8.36 (dd, J=4.4, 1.2 Hz, 1H), 8.01 (d, J=6.4 Hz, 1H), 7.76(dd, J=8.0, 1.6 Hz, 1H), 7.41-7.31 (m, 6H), 5.50 (s, 2H), 5.00-4.88 (m,2H), 3.40 (s, 3H), 1.31 (d, J=6.4 Hz, 3H). LC-MS (Method D): m/z=393.15[M+H]⁺, 1.553 min.

Example 137:(S)-4-Fluoro-1-((5-fluoropyridin-3-yl)methyl)-N-(5-methyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepin-3-yl)-1H-pyrazole-3-carboxamide

Step 1: Preparation of 3-(bromomethyl)-5-fluoropyridine

Tribromophosphine (853 mg, 3.15 mmol) was added to a solution of(5-fluoropyridin-3-yl)methanol (200 mg, 1.57 mmol) in dichloromethane (2mL). The reaction mixture was stirred overnight at room temperature. Thesolvent was evaporated under vacuum to afford the title compound (150 mgcrude). LC-MS (Method S): m/z=190.1 [M+H]⁺, 0.787 min.

Step 2: Preparation of(S)-4-fluoro-1-((5-fluoropyridin-3-yl)methyl)-N-(5-methyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepin-3-yl)-1H-pyrazole-3-carboxamide

Potassium carbonate (181 mg, 1.31 mmol) was added to a mixture of(S)-4-fluoro-N-(5-methyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepin-3-yl)-1H-pyrazole-3-carboxamide(80 mg, 0.26 mmol) and 3-(bromomethyl)-5-fluoropyridine (107 mg, 0.39mmol) in N,N-dimethylformamide (2 mL). The resulting mixture was stirredat room temperature for 3 hours, diluted with water (2 mL) and extractedwith ethyl acetate (3×30 mL). The combined organic layers were washedwith brine, dried over anhydrous sodium sulfate, filtered andconcentrated to dryness under vacuum. The residue was purified byPrep-HPLC with the following conditions: Column: XBridge C18 OBD PrepColumn, 100 Å, 5 μm, 19 mm×250 mm; Mobile Phase A: water (10 mmol/LNH₄HCO₃); Mobile Phase B: ACN; Flow rate: 20 mL/min; Gradient: 15% B to35% B over 7 min; UV 254 & 220 nm; Rt: 7 min to afford the titlecompound. ¹H NMR (400 MHz, DMSO-d₆) δ 8.59 (d, J=2.8 Hz, 1H), 8.46 (s,1H), 8.37 (dd, J=4.8, 1.6 Hz, 1H), 8.30 (d, J=8.0 Hz, 1H), 8.20 (d,J=4.4 Hz, 1H), 7.72-7.67 (m, 2H), 7.36-7.32 (m, 1H), 5.46 (s, 2H),4.88-4.81 (m, 1H), 4.70-4.64 (m, 1H), 4.54-4.49 (m, 1H), 3.36 (s, 3H).LC-MS (Method T): m/z=415.2 [M+H]⁺, 1.057 min.

Example 138:N-((2R,3S)-2,5-dimethyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepin-3-yl)-5-(1-phenylcyclopropyl)-1,3,4-oxadiazole-2-carboxamide

The crude product obtained using the procedure described in Example 54was purified by Prep-HPLC with the following conditions: Column: XBridgeC18 OBD Prep Column, 100 Å, 5 μm, 19 mm×250 mm; Mobile Phase A: water(10 mmol/L NH₄HCO₃); Mobile Phase B: ACN; Flow rate: 20 mL/min;Gradient: 40% B to 60% B in 7 min; UV 254 & 220 nm; Rt: 7 min to affordthe title compound. ¹H NMR (300 MHz, DMSO-d₆) δ 8.58 (s, 1H), 8.36 (dd,J=4.5, 1.5 Hz, 1H), 7.74 (dd, J=8.1, 1.5 Hz, 1H), 7.44-7.29 (m, 6H),4.96-4.90 (m, 2H), 3.40 (s, 3H), 1.72-1.68 (m, 2H), 1.56-1.52 (m, 2H),1.39-1.36 (m, 3H). LC-MS (Method D): m/z=420.15 [M+H]⁺, 1.777 min.

Example 139:N-((2R,3S)-2,5-dimethyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepin-3-yl)-5-(2-fluorophenoxy)pyridazine-3-carboxamide

The crude product obtained using the procedure described in Example 54was purified by Prep-HPLC with the following conditions: Column: XBridgeShield RP18 OBD Column, 5 mm, 19×150 mm; Mobile Phase A: water (10mmol/L NH₄HCO₃); Mobile Phase B: ACN; Flow rate: 20 mL/min; Gradient:25% B to 50% B over 7 min; UV 254 & 220 nm; Rt: 6.5 min to afford thetitle compound. ¹H NMR (300 MHz, DMSO-d₆) δ 9.48 (d, J=3.0 Hz, 1H), 8.89(d, J=6.3 Hz, 1H), 8.36 (dd, J=4.8, 1.8 Hz, 1H), 7.77 (dd, J=7.8, 1.5Hz, 1H), 7.58-7.34 (m, 5H), 7.27 (dd, J=3.0, 0.9 Hz, 1H), 5.05-4.93 (m,2H), 3.42 (s, 3H), 1.35 (d, J=5.7 Hz, 3H). LC-MS (Method D): m/z=424.1[M+H]⁺, 1.747 min.

Example 140:1-Benzyl-N-((2R,3S)-2,5-dimethyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepin-3-yl)-1H-imidazole-4-carboxamide

Step 1: Preparation of ethyl 1-benzyl-1H-imidazole-4-carboxylate

Sodium hydride (60%, 0.51 g, 21.3 mmol) was added to a stirring solutionof ethyl 1H-imidazole-4-carboxylate (2.0 g, 14.3 mmol) inN,N-dimethylformamide (15 mL). The resulting mixture was stirred for 30minutes at 0° C. followed by the addition of (bromomethyl)benzene (2.93g, 17.13 mmol). After stirring at room temperature for 1.5 hours, thereaction mixture was quenched by the addition of water (30 mL) andextracted with ethyl acetate (3×100 mL). The combined organic layerswere washed with brine, dried over anhydrous sodium sulfate, filteredand concentrated under vacuum. The residue was purified by columnchromatography (ethyl acetate/petroleum ether, 1/1) to afford the titlecompound (1.0 g, 30%) as a yellow oil. LC-MS (Method C): m/z=231.1[M+H]⁺, 0.985 min.

Step 2: Preparation of1-benzyl-N-((2R,3S)-2,5-dimethyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepin-3-yl)-1H-imidazole-4-carboxamide

The crude product obtained using the procedure described in Example 54was purified by Prep-HPLC with the following conditions: Column, XBridgeShield RP18 OBD, 5 μm, 19×150 mm; Mobile Phase A: water (10 mmol/LNH₄HCO₃); Mobile Phase B: ACN; Flow rate: 20 mL/min; Gradient: 30% B to55% B over 7 min; Detector: UV 254 & 220 nm to afford the titlecompound. ¹H NMR (400 MHz, DMSO-d₆) δ 8.33 (dd, J=4.4, 1.2 Hz, 1H), 7.89(d, J=1.2 Hz, 1H), 7.78-7.71 (m, 3H), 7.37-7.27 (m, 6H), 5.21 (s, 2H),4.92-4.84 (m, 2H), 3.37 (s, 3H), 1.28 (d, J=6.0 Hz, 3H). LC-MS (MethodF): m/z=392.0 [M+H]⁺, 1.029 min.

Example 141A and 141B:(S)-5-Benzyl-N-(6,7-dihydroimidazo[1,2-d]pyrido[3,2-b][1,4]oxazepin-7-yl)-4H-1,2,4-triazole-3-carboxamideand(R)-5-benzyl-N-(6,7-dihydroimidazo[1,2-d]pyrido[3,2-b][1,4]oxazepin-7-yl)-4H-1,2,4-triazole-3-carboxamide

Step 1: Preparation of 2-chloro-1-(1-trityl-1H-imidazol-2-yl)ethanone

A solution of n-butyllithium in hexane (2.5 M, 13.2 mL, 33.0 mmol) wasadded to a stirred mixture of 1-trityl-1H-imidazole (9.3 g, 30.0 mmol)in tetrahydrofuran (190 mL) dropwise at −78° C. under a nitrogenatmosphere. After the addition was complete, the reaction mixture waswarmed to −10° C. slowly and stirred for 1 hour. Then the mixture wascooled to −78° C. again and a solution of tert-butyl 2-chloroacetate(5.4 g, 36.0 mol) in tetrahydrofuran (10 mL) was added in one portion.The resulting mixture was warmed to room temperature with stirring over2-3 hours, quenched with ice-water (100 mL) and extracted with ethylacetate (3×100 mL). The combined organic layers were washed with brine,dried over anhydrous sodium sulfate, filtered and concentrated undervacuum. The residue was purified by column chromatography (ethylacetate/petroleum ether, 1/4) to afford the title compound (900 mg,7.8%) as a yellow solid.

Step 2: Preparation of2-(2-bromopyridin-3-yloxy)-1-(1-trityl-1H-imidazol-2-yl)ethanone

2-Chloro-1-(1-trityl-1H-imidazol-2-yl)ethanone (772.0 mg, 2.0 mmol) wasadded to a stirred mixture of 2-bromopyridin-3-ol (346.0 mg, 2.0 mmol)and potassium carbonate (414.0 mg, 3.0 mmol) in acetonitrile (10 mL)under a nitrogen atmosphere. The resulting mixture was heated to refluxand stirred for 2 hours. After cooling to room temperature, the reactionmixture was diluted with water (20 mL) and extracted with ethyl acetate(3×20 mL). The combined organic layers were washed with brine, driedover anhydrous sodium sulfate, filtered and concentrated under vacuum.The residue was purified by column chromatography (ethylacetate/petroleum ether, 1/3) to afford the title compound (700 mg,66.9%) as a yellow solid. LC-MS (Method C): m/z=524.1 [M+H]⁺, 1.490 min.

Step 3: Preparation of2-(2-bromopyridin-3-yloxy)-1-(H-imidazol-2-yl)ethanone

A mixture of2-(2-bromopyridin-3-yloxy)-1-(1-trityl-1H-imidazol-2-yl)ethanone (700mg, 1.34 mmol) in methanol/acetic acid (5 mL/1 mL) was heated at refluxand stirred overnight. After cooling to room temperature, the resultingmixture was concentrated under high vacuum. The residue was purified bycolumn chromatography (ethyl acetate/petroleum ether, 1/1) to afford thetitle compound (300 mg, 79.7%) as a yellow solid. LC-MS (Method R):m/z=282.2 [M+H]⁺, 0.628 min.

Step 4: Preparation ofimidazo[1,2-d]pyrido[3,2-b][1,4]oxazepin-7(6H)-one

Cuprous iodide (19 mg, 0.1 mmol) was added to a mixture of2-(2-bromopyridin-3-yloxy)-1-(1H-imidazol-2-yl)ethanone (281 mg, 1.0mmol), L-proline (23.1 mg, 0.2 mmol) and potassium carbonate (345 mg,2.50 mmol) in toluene (10 mL) under a nitrogen atmosphere. The resultingmixture was stirred overnight at 100° C. After cooling to roomtemperature, the reaction mixture was diluted with saturated aqueousammonium chloride (20 mL) and extracted with dichloromethane/methanol(10/1) (3×20 mL). The combined organic layers were dried over anhydroussodium sulfate, filtered and concentrated under vacuum. The residue waspurified by column chromatography (methanol/dichloromethane, 1/40) toafford the title compound (70 mg, 34.8%) as a yellow solid. LC-MS(Method R): m/z=202.3 [M+H]⁺, 0.540 min.

Step 5: Preparation of6,7-dihydroimidazo[1,2-d]pyrido[3,2-b][1,4]oxazepin-7-amine

Sodium cyanoborohydride (11.0 mg, 0.17 mmol) was added to a stirringmixture of imidazo[1,2-d]pyrido[3,2-b][1,4]oxazepin-7(6H)-one (50.0 mg,0.29 mmol) and ammonium acetate (383.0 mg, 4.98 mmol) in methanol (5mL). The resulting mixture was stirred overnight at room temperature.The reaction mixture was concentrated under vacuum. The residue waspurified by column chromatography (methanol/dichloromethane, 1/15) toafford the title compound (30 mg, 59.4%) as a yellow solid. LC-MS(Method C): m/z=203.1 [M+H]⁺, 0.778 min.

Step 7. Preparation of5-benzyl-N-(6,7-dihydroimidazo[1,2-d]pyrido[3,2-b][1,4]oxazepin-7-yl)-4H-1,2,4-triazole-3-carboxamide

The crude product obtained using Amide Coupling Procedure C was purifiedby Prep-TLC (ethyl acetate/petroleum ether, 3/1) to afford the titlecompound (16 mg, 27.6%) as a white solid. LC-MS (Method C): m/z=388.1[M+H]⁺, 0.921 min.

Step 7. Preparation of(S)-5-benzyl-N-(6,7-dihydroimidazo[1,2-d]pyrido[3,2-b][1,4]oxazepin-7-yl)-4H-1,2,4-triazole-3-carboxamide(141A) and(R)-5-benzyl-N-(6,7-dihydroimidazo[1,2-d]pyrido[3,2-b][1,4]oxazepin-7-yl)-4H-1,2,4-triazole-3-carboxamide(141B)

The racemate of5-benzyl-N-(6,7-dihydroimidazo[1,2-d]pyrido[3,2-b][1,4]oxazepin-7-yl)-4H-1,2,4-triazole-3-carboxamide(16 mg, 0.041 mmol) was separated by Prep-Chiral-HPLC with the followingconditions: Column: Chiralpak IC, 2×25 cm, 5 μm; Mobile Phase A: hexane,Mobile Phase B: EtOH; Flow rate: 16 mL/min; Gradient: 50% B to 50% Bover 30 min; UV254 & 220 nm; Rt 1: 16.881; Rt 2: 24.391 to afford thetitle compounds:

Example 141A (first eluting isomer): ¹H NMR (400 MHz, CD₃OD-d₄) δ 8.43(s, 1H), 8.31 (dd, J=4.4, 1.2 Hz, 1H), 7.70 (dd, J=8.0, 1.2 Hz, 1H),7.42 (dd, J=8.0, 4.4 Hz, 1H), 7.33-7.22 (m, 6H), 5.86 (s, 1H), 4.59-4.48(m, 2H), 4.15 (s, 2H). LC-MS (Method D): m/z=388.1 [M+H]⁺, 1.139 min.

Example 141B (second eluting isomer): ¹H NMR (400 MHz, CD₃OD-d₄) δ 8.37(s, 1H), 8.29 (dd, J=4.4, 1.6 Hz, 1H), 7.67 (dd, J=8.0, 1.2 Hz, 1H),7.38 (dd, J=8.0, 4.4 Hz, 1H), 7.32-7.20 (m, 6H), 5.83 (s, 1H), 4.57-4.47(m, 2H), 4.10 (s, 2H). LC-MS (Method D): m/z=388.1 [M+H]⁺, 1.139 min.

Example 142:(S)-1-Benzyl-N-(5-methyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepin-3-yl)isoxazole-3-carboxamide

The crude product obtained using Amide Coupling Procedure C was purifiedby Prep-HPLC with the following conditions: Column: XBridge Shield RP18OBD Column, 5 μm, 19×150 mm; Mobile Phase A: water (10 mmol/L NH₄HCO₃),Mobile Phase B: ACN; Flow rate: 20 mL/min; Gradient: 25% B to 50% B over7 min; UV 254 & 220 nm; Rt: 5.6 min to afford the title compound. ¹H NMR(300 MHz, DMSO-d₆) δ 8.94 (d, J=7.8 Hz, 1H), 8.33 (dd, J=4.8, 1.5 Hz,1H), 7.66 (dd, J=7.8, 1.5 Hz, 1H), 7.35-7.21 (m, 6H), 6.52 (s, 1H),4.86-4.77 (m, 1H), 4.67-4.59 (m, 1H), 4.51-4.44 (m, 1H), 4.19 (s, 2H),3.31 (s, 3H). LC-MS (Method D): m/z=379.1 [M+H]⁺, 1.719 min.

Example 143:N-((2R,3S)-2,5-dimethyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepin-3-yl)-4-fluoro-1-(4-fluorobenzyl)-1H-pyrazole-3-carboxamide

The crude product obtained using the procedure described in Example 54was purified by Prep-HPLC with the following conditions: Column: XBridgeShield RP18 OBD Column, 5 μm, 19×150 mm; Mobile Phase A: water (10mmol/L NH₄HCO₃), Mobile Phase B: ACN; Flow rate: 20 mL/min; Gradient:25% B to 65% B over 7 min; UV 254 & 220 nm; Rt: 5 min to afford thetitle compound (26.2 mg, 28%) as a white solid. ¹H NMR (300 MHz,DMSO-d₆) δ 8.32 (dd, J=4.8, 1.5 Hz, 1H), 8.10 (d, J=4.5 Hz, 1H), 7.71(dd, J=7.8, 1.5 Hz, 1H), 7.56 (d, J=6.6 Hz, 1H), 7.35-7.29 (m, 3H),7.22-7.14 (m, 2H), 5.31 (s, 2H), 4.94-4.83 (m, 2H), 3.36 (s, 3H), 1.27(d, J=6.3 Hz, 3H). LC-MS (Method D): m/z=428.1 [M+H]⁺, 1.771 min.

Example 144:(S)-1-(3-cyanobenzyl)-4-fluoro-N-(5-methyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepin-3-yl)-1H-pyrazole-3-carboxamide

The crude product obtained using Amide Coupling Procedure C was purifiedby Prep-HPLC with the following conditions: Column: XBridge Shield RP 18OBD Column, 5 μm, 19×150 mm; Mobile Phase A: water (10 mmol/L NH₄HCO₃),Mobile Phase B: ACN; Flow rate: 20 mL/min; Gradient: 25% B to 50% B over7 min; UV 254 & 220 nm; Rt: 5.5 min to afford the title compound. ¹H NMR(300 MHz, DMSO-d₆) δ 8.32 (dd, J=4.8, 1.5 Hz, 1H), 8.22 (d, J=7.8 Hz,1H), 8.14 (d, J=4.2 Hz, 1H), 7.81-7.74 (m, 2H), 7.68-7.64 (m, 1H),7.61-7.55 (m, 2H), 7.32-7.27 (m, 1H), 5.39 (s, 2H), 4.85-4.76 (m, 1H),4.67-4.59 (m, 1H), 4.50-4.44 (m, 1H), 3.32 (s, 3H). LC-MS (Method D):m/z=421.1 [M+H]⁺, 1.550 min.

Example 145A and 145B:(S)—N-(9-methyl-8-oxo-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]azepin-7-yl)-5-(1-phenylcyclopropyl)-1,3,4-oxadiazole-2-carboxamideand(R)—N-(9-methyl-8-oxo-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]azepin-7-yl)-5-(1-phenylcyclopropyl)-1,3,4-oxadiazole-2-carboxamide

Step 1: Preparation ofN-(9-methyl-8-oxo-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]azepin-7-yl)-5-(1-phenylcyclopropyl)-1,3,4-oxadiazole-2-carboxamide

The crude product obtained using the procedure described in Example 54was purified by Prep-HPLC: Column: XBridge Shield RP18 OBD, 19×150 mm, 5μm; Mobile phase: Phase A: water (10 mmol/L NH₄HCO₃); Phase B: ACN(35.0% ACN to 41.0% over 7 min); Detector, UV220 & 254 nm; Rt: 5.88 minto afford the title compound (45 mg, 25.4%) as a white solid. LC-MS(Method E): m/z=404.00 [M+H]⁺, 0.833 min.

Step 2: Preparation of(S)—N-(9-methyl-8-oxo-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]azepin-7-yl)-5-(1-phenylcyclopropyl)-1,3,4-oxadiazole-2-carboxamide(First Eluting Isomer) and(R)—N-(9-methyl-8-oxo-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]azepin-7-yl)-5-(1-phenylcyclopropyl)-1,3,4-oxadiazole-2-carboxamide(Second Eluting Isomer)

The racemate ofN-(9-methyl-8-oxo-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]azepin-7-yl)-5-(1-phenylcyclopropyl)-1,3,4-oxadiazole-2-carboxamide(45 mg, 0.11 mmol) was separated by Prep-Chiral-HPLC with the followingconditions: Column: Chiralpak IA, 5 μm, 2.12×15 cm; Mobile Phase A:hexane, Mobile Phase B: IPA; Flow rate: 20 mL/min; Gradient: 50% B to50% B over 13.5 min; UV 220 & 254 nm; Rt 1: 8.78; Rt 2: 11.03 to affordthe title compounds:

Example 145A (first eluting isomer): ¹H NMR (400 MHz, Methanol-d₄) δ8.41 (dd, J=4.9, 1.8 Hz, 1H), 7.78 (dd, J=7.5, 1.8 Hz, 1H), 7.45-7.42(m, 2H), 7.38-7.25 (m, 4H), 4.48-4.44 (m, 1H), 3.45 (s, 3H), 2.91-2.76(m, 2H), 2.60-2.49 (m, 1H), 2.37-2.28 (m, 1H), 1.77-1.74 (m, 2H),1.55-1.53 (m, 2H). LC-MS (Method X): m/z=404.10 [M+H]⁺, 1.180 min.

Example 145B (second eluting isomer): ¹H NMR (400 MHz, Methanol-d₄) δ8.41 (dd, J=4.9, 1.8 Hz, 1H), 7.79 (dd, J=7.6, 1.8 Hz, 1H), 7.46-7.42(m, 2H), 7.38-7.25 (m, 4H), 4.49-4.44 (m, 1H), 3.45 (s, 3H), 2.90-2.77(m, 2H), 2.60-2.49 (m, 1H), 2.37-2.28 (m, 1H), 1.77-1.74 (m, 2H),1.55-1.53 (m, 2H). LC-MS (Method X): m/z=404.00 [M+H]⁺, 1.179 min.

Example 146:(S)-5-benzyl-N-(5-methyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepin-3-yl)-1,3,4-oxadiazole-2-carboxamide

The crude product obtained using the procedure described in Example 54was purified by Prep-HPLC with the following conditions: Column: XBridgeShield RP18 OBD Column, 5 mm, 19×150 mm; Mobile Phase A: water (10mmol/L NH₄HCO₃), Mobile Phase B: ACN; Flow rate: 20 mL/min; Gradient:35% B to 65% B over 7 min; UV 254 & 220 nm; Rt: 5 min to afford thetitle compound. ¹H NMR (300 MHz, DMSO-d₆) δ 9.50 (s, 1H), 8.33 (dd,J=4.8, 1.5 Hz, 1H), 7.69-7.65 (m, 1H), 7.38-7.24 (m, 6H), 4.84-4.65 (m,2H), 4.53-4.47 (m, 1H), 4.34 (s, 2H), 3.31 (s, 3H). LC-MS (Method D):m/z=380.1 [M+H]⁺, 1.531 min.

Example 147:5-benzyl-N-((2R,3S)-2,5-dimethyl-8-(methylsulfonyl)-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepin-3-yl)-4H-1,2,4-triazole-3-carboxamide

Step 1: Preparation of tert-butyl(2R,3S)-8-bromo-2-methyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepin-3-ylcarbamate

Bromine (1.63 g, 10.2 mmol) was added to a stirring mixture oftert-butyl(2R,3S)-2-methyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepin-3-ylcarbamate(1.0 g, 3.4 mmol) in N,N-dimethylformamide (30 mL). The reaction mixturewas stirred at room temperature for 4 hours and quenched by the additionof aqueous sodium thiosulfate (5%, 20 mL). The resulting solution wasextracted with ethyl acetate (3×50 mL). The combined organic layers werewashed with brine, dried over anhydrous sodium sulfate, filtered andconcentrated under vacuum. The residue was purified by columnchromatography (ethyl acetate/petroleum ether, 1/4) to afford the titlecompound (900 mg, 71%) as a white solid. LC-MS (Method C): m/z=372.0[M+H]⁺, 1.283 min.

Step 2: Preparation of tert-butyl(2R,3S)-8-bromo-2,5-dimethyl-4-oxo-2,3,4,5-tetrahydro-pyrido[3,2-b][1,4]oxazepin-3-ylcarbamate

Iodomethane (306 mg, 2.2 mmol) was added to a stirring mixture oftert-butyl(2R,3S)-8-bromo-2-methyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepin-3-ylcarbamate(800 mg, 2.2 mmol) and cesium carbonate (703 mg, 2.2 mmol) inN,N-dimethylformamide (20 mL). The reaction mixture was stirred for 2hours at room temperature, diluted with water (50 mL) and extracted withethyl acetate (3×50 mL). The combined organic layers were washed withbrine, dried over anhydrous sodium sulfate, filtered and concentratedunder vacuum. The residue was purified by column chromatography (ethylacetate/petroleum ether, 1/6) to afford the title compound (650 mg, 79%)as a white solid. LC-MS (Method C): m/z=330.0 [M+H-56]⁺, 1.408 min.

Step 3: Preparation of tert-butyl(2R,3S)-2,5-dimethyl-8-(methylsulfonyl)-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepin-3-ylcarbamate

A solution of isopropylmagnesium chloride in tetrahydrofuran (2.0 M,0.52 mL, 1.04 mmol) was added to a stirring mixture of tert-butyl(2R,3S)-8-bromo-2,5-dimethyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepin-3-ylcarbamate(200 mg, 0.52 mmol) in tetrahydrofuran (5 mL) at 0° C. The reactionmixture was stirred for 1 hour at 0° C. followed by the addition ofmethanesulfonyl chloride (60 mg, 0.52 mmol). The reaction mixture wasstirred for another 2 hours at room temperature, diluted with water (15mL) and extracted with ethyl acetate (3×50 mL). The combined organiclayers were washed with brine, dried over anhydrous sodium sulfate,filtered and concentrated under vacuum. The residue was purified bycolumn chromatography (ethyl acetate/petroleum ether, 1/4) to afford thetitle compound (55 mg, 28%) as a white solid. LC-MS (Method C):m/z=330.1 [M+H-56]⁺, 1.208 min.

Step 4: Preparation of(2R,3S)-3-amino-2,5-dimethyl-8-(methylsulfonyl)-2,3-dihydropyrido-[3,2-b][1,4]oxazepin-4(5H)-onehydrochloride

To a stirring mixture of tert-butyl(2R,3S)-2,5-dimethyl-8-(methylsulfonyl)-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepin-3-ylcarbamate(55 mg, 0.15 mmol) in 1,4-dioxane (5 mL) was added a solution ofhydrogen chloride in 1,4-dioxane (4 M, 2 mL, 8 mmol). The reactionmixture was stirred for 2 hours at room temperature and concentratedunder high vacuum to afford the title compound (46 mg crude) as a whitesolid, which was used directly in the next step without furtherpurification. LC-MS (Method C): m/z=286.1 [M+H]⁺, 0.783 min.

Step 5: Preparation of5-benzyl-N-((2R,3S)-2,5-dimethyl-8-(methylsulfonyl)-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepin-3-yl)-4H-1,2,4-triazole-3-carboxamide

The crude product obtained using Amide Coupling Procedure C was purifiedby Prep-HPLC with the following conditions: Column: XBridge C18 OBD PrepColumn, 100 Å, 5 μm, 19 mm×250 mm; Mobile Phase A: water (10 mmol/LNH₄HCO₃), Mobile Phase B: ACN; Flow rate: 20 mL/min; Gradient: 40% B to60% B over 7 min; UV 254 & 220 nm; Rt: 7 min to afford the titlecompound. ¹H NMR (400 MHz, DMSO-d₆) δ 14.40 (s, 1H), 8.81 (d, J=2.0 Hz,1H), 8.22 (d, J=2.0 Hz, 1H), 8.01 (br s, 1H), 7.36-7.21 (m, 5H),5.15-5.04 (m, 2H), 4.16 (s, 2H), 3.45 (s, 3H), 3.39 (s, 3H), 1.35 (d,J=6.4 Hz, 3H). LC-MS (Method D): m/z=471.1 [M+H]⁺, 1.519 min.

Example 148A and 148B:(S)-5-benzyl-N-(9-methyl-8-oxo-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]azepin-7-yl)-1,3,4-oxadiazole-2-carboxamideand(R)-5-benzyl-N-(9-methyl-8-oxo-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]azepin-7-yl)-1,3,4-oxadiazole-2-carboxamide

Step 1: Preparation of5-benzyl-N-(9-methyl-8-oxo-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]azepin-7-yl)-1,3,4-oxadiazole-2-carboxamide

The crude product obtained using the procedure described in Example 54was purified by Prep-HPLC with the following conditions: Column: XSelectCSH Prep C18 OBD Column, 5 mm, 19×150 mm; Mobile Phase A: water (0.1%formic acid); Mobile Phase B: ACN; Flow rate: 20 mL/min; Gradient: 40% Bto 52% B over 4 min; UV 254 & 220 nm; Rt: 4 min to afford the titlecompound (20 mg, 14.2%) as a white solid. LC-MS (Method D): m/z=378.1[M+H]⁺, 1.492 min.

Step 2: Preparation of(S)-5-benzyl-N-(9-methyl-8-oxo-6,7,8,9-tetrahydro-1H-pyrido[2,3-b]azepin-7-yl)-1,3,4-oxadiazole-2-carboxamide(First Eluting Isomer) and(R)-5-benzyl-N-(9-methyl-8-oxo-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]azepin-7-yl)-1,3,4-oxadiazole-2-carboxamide(Second Eluting Isomer)

The racemate of5-benzyl-N-(9-methyl-8-oxo-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]azepin-7-yl)-1,3,4-oxadiazole-2-carboxamide(20 mg) was separated by Prep-Chiral-HPLC with the following conditions:Column: CHIRALPAK IA, 2.12×15 cm, 5 μm; Mobile Phase A: hexane; MobilePhase B: IPA; Flow rate: 20 mL/min; Gradient: 50% B to 50% B over 12min; UV 254 & 220 nm; Rt 1: 7.106; Rt 2: 9.363 min to afford the titlecompounds:

Example 148A (first eluting isomer): ¹H NMR (300 MHz, CD₃OD-d₄) δ 8.44(dd, J=5.1, 1.8 Hz, 1H), 7.81 (dd, J=7.5, 1.5 Hz, 1H), 7.38-7.26 (m,6H), 4.54-4.46 (m, 1H), 4.34 (s, 2H), 3.48 (s, 3H), 2.90-2.78 (m, 2H),2.65-2.51 (m, 1H), 2.41-2.97 (m, 1H). LC-MS (Method D): m/z=378.1[M+H]⁺, 1.492 min.

Example 148B (second eluting isomer): ¹H NMR (300 MHz, CD₃OD-d₄) δ 8.41(dd, J=4.8, 1.8 Hz, 1H), 7.78 (dd, J=7.2, 1.5 Hz, 1H), 7.39-7.21 (m,6H), 4.52-4.41 (m, 1H), 4.31 (s, 2H), 3.45 (s, 3H), 2.91-2.75 (m, 2H),2.64-2.45 (m, 1H), 2.41-2.25 (m, 1H). LC-MS (Method D): m/z=378.1[M+H]⁺, 1.496 min.

Example 149:(S)-5-(2-fluorophenoxy)-N-(5-methyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepin-3-yl)pyridazine-3-carboxamide

The crude product obtained using the procedure described in Example 54was purified by Prep-HPLC with the following conditions: Column: XBridgeC18 OBD Prep Column, 100 Å, 5 mm, 19 mm×250 mm; Mobile Phase A: water(10 mmol/L NH₄HCO₃), Mobile Phase B: ACN; Flow rate: 20 mL/min;Gradient: 40% B to 60% B over 7 min; UV 254 & 220 nm; Rt: 6.5 min toafford the title compound. ¹H NMR (300 MHz, DMSO-d₆) δ 9.45-9.42 (m,2H), 8.34-8.31 (m, 1H), 7.69-7.65 (m, 1H), 7.53-7.38 (m, 3H), 7.37-7.27(m, 2H), 7.22 (d, J=3.6 Hz, 1H), 4.91-4.74 (m, 2H), 4.56-4.50 (m, 1H),3.32 (s, 3H). LC-MS (Method V): m/z=410.1 [M+H]⁺, 2.765 min.

Example 150:5-benzyl-N-((2R,3S)-8-cyano-2,5-dimethyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepin-3-yl)-4H-1,2,4-triazole-3-carboxamide

Step 1: Preparation of tert-butyl(2R,3S)-8-cyano-2,5-dimethyl-4-oxo-2,3,4,5-tetrahydropyrido-[3,2-b][1,4]oxazepin-3-ylcarbamate

Tetrakis(triphenylphosphanyl)palladium (60 mg, 0.052 mmol) was added toa suspension of zinc cyanide (80 mg, 0.68 mmol) and tert-butyl(2R,3S)-8-bromo-2,5-dimethyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepin-3-ylcarbamate(200 mg, 0.52 mmol) in N,N-dimethylformamide (2 mL) under a nitrogenatmosphere. The reaction mixture was heated at 140° C. under microwaveand stirred for 3 hours. The reaction mixture was filtered, and thefiltrate was concentrated under vacuum. The residue was purified bycolumn chromatography (ethyl acetate/petroleum ether, 1/3) to afford thetitle compound (110 mg, 64%) as a white solid. LC-MS (Method C):m/z=277.1 [M+H-56]⁺, 1.300 min.

Step 2: Preparation of(2R,3S)-3-amino-2,5-dimethyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepine-8-carbonitrilehydrochloride

To a solution of tert-butyl(2R,3S)-8-cyano-2,5-dimethyl-4-oxo-2,3,4,5-tetrahydro-pyrido[3,2-b][1,4]oxazepin-3-ylcarbamate(68 mg, 0.21 mmol) in 1,4-dioxane (5 mL) was added a solution ofhydrogen chloride in 1,4-dioxane (4 M, 2 mL, 8 mmol). The resultingmixture was stirred for 2 hours at room temperature and concentratedunder high vacuum to afford the title compound (55 mg crude) as a whitesolid, which was used directly in the next step without furtherpurification. LC-MS (Method C): m/z=233.1 [M+H]⁺, 0.825 min.

Step 3: Preparation of5-benzyl-N-((2R,3S)-8-cyano-2,5-dimethyl-4-oxo-2,3,4,5-tetrahydro-pyrido[3,2-b][1,4]oxazepin-3-yl)-4H-1,2,4-triazole-3-carboxamide

The crude product obtained using Amide Coupling Procedure C was purifiedby Prep-HPLC with the following conditions: Column: XSelect CSH Prep C18OBD Column, 5 μm, 19×150 mm; Mobile Phase A: water (0.1% formic acid),Mobile Phase B: ACN; Flow rate: 20 mL/min; Gradient: 30% B to 65% B over7 min; UV 254 & 220 nm; Rt: 6 min to afford the title compound. ¹H NMR(400 MHz, DMSO-d₆) δ 14.43 (s, 1H), 8.82 (d, J=1.6 Hz, 1H), 8.31 (d,J=2.0 Hz, 1H), 8.00 (br s, 1H), 7.36-7.23 (m, 5H), 5.08-5.01 (m, 2H),4.15 (s, 2H), 3.42 (s, 3H), 1.33 (d, J=6.0 Hz, 3H). LC-MS (Method F):m/z=418.0 [M+H]⁺, 1.187 min.

Example 151:(S)-5-benzyl-4-cyano-N-(5-methyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepin-3-yl)thiazole-2-carboxamide

The crude product obtained using the procedure described in Example 54was purified by Prep-HPLC with the following conditions: Column: XBridgePrep C18 OBD Column 5 μm, 19×150 mm; Mobile Phase A: water (10 mmol/LNH₄HCO₃), Mobile Phase B: ACN; Flow rate: 20 mL/min; Gradient: 25% B to55% B over 7 min; 254 nm; Rt: 6.32 min to afford the title compound. ¹HNMR (400 MHz, CD₃OD-d₄) δ 8.35 (dd, J=4.8, 1.6 Hz, 1H), 7.67 (dd, J=8.0,1.6 Hz, 1H), 7.43-7.26 (m, 6H), 4.98 (dd, J=11.5, 7.4 Hz, 1H), 4.70-4.55(m, 2H), 4.42 (s, 2H), 3.48 (s, 3H). LC-MS (Method Q): m/z=420.3 [M+H]⁺,1.503 min.

Example 152A and 152B:(R)-1-(3-cyanobenzyl)-4-fluoro-N-(9-methyl-8-oxo-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]azepin-7-yl)-1H-pyrazole-3-carboxamideand(S)-1-(3-cyanobenzyl)-4-fluoro-N-(9-methyl-8-oxo-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]azepin-7-yl)-1H-pyrazole-3-carboxamide

Step 1: Preparation of1-(3-cyanobenzyl)-4-fluoro-N-(9-methyl-8-oxo-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]azepin-7-yl)-1H-pyrazole-3-carboxamide

The crude product obtained using Amide Coupling Procedure C was purifiedby Prep-HPLC with the following conditions: Column: XBridge C18 OBD PrepColumn, 100 Å, 5 μm, 19 mm×250 mm; Mobile Phase A: water (10 mmol/LNH₄HCO₃), Mobile Phase B: ACN; Flow rate: 20 mL/min; Gradient: 20% B to50% B over 7 min; UV 254 & 220 nm; Rt: 7 min to afford the titlecompound (65 mg, 60%) as a white solid. LC-MS (Method D): m/z=419.1[M+H]⁺, 1.508 min.

Step 2: Preparation of(R)-1-(3-cyanobenzyl)-4-fluoro-N-(9-methyl-8-oxo-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]azepin-7-yl)-1H-pyrazole-3-carboxamide(First Eluting Isomer) and(S)-1-(3-cyanobenzyl)-4-fluoro-N-(9-methyl-8-oxo-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]azepin-7-yl)-1H-pyrazole-3-carboxamide(Second Eluting Isomer)

The racemate of1-(3-cyanobenzyl)-4-fluoro-N-(9-methyl-8-oxo-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]azepin-7-yl)-1H-pyrazole-3-carboxamide(65 mg, 0.16 mmol) was separated by Prep-Chiral-HPLC with the followingconditions: Column: Chiralpak ID-2, 5 μm, 2×25 cm; Mobile Phase A:hexane, Mobile Phase B: EtOH; Flow rate: 16 mL/min; Gradient: 60% B to60B % over 20 min; UV 254 & 220 nm; Rt 1: 12.92 min; Rt 2: 16.60 min toafford the title compounds:

Example 152A (first eluting isomer): ¹H NMR (400 MHz, DMSO-d₆) δ 8.44(dd, J=4.8, 1.6 Hz, 1H), 8.16 (d, J=4.4 Hz, 1H), 8.08 (d, J=7.6 Hz, 1H),7.85-7.78 (m, 3H), 7.64-7.58 (m, 2H), 7.30-7.26 (m, 1H), 5.42 (s, 2H),4.34-4.26 (m, 1H), 3.35 (s, 3H), 2.78-2.65 (m, 2H), 2.43-2.25 (m, 2H).LC-MS (Method F): m/z=419.0 [M+H]⁺, 1.070 min.

Example 152B (second eluting isomer): ¹H NMR (400 MHz, DMSO-d₆) δ 8.44(dd, J=4.8, 1.6 Hz, 1H), 8.16 (d, J=4.4 Hz, 1H), 8.08 (d, J=7.6 Hz, 1H),7.85-7.78 (m, 3H), 7.64-7.58 (m, 2H), 7.30-7.26 (m, 1H), 5.42 (s, 2H),4.34-4.26 (m, 1H), 3.35 (s, 3H), 2.78-2.64 (m, 2H), 2.43-2.24 (m, 2H).LC-MS (Method F): m/z=419.1 [M+H]⁺, 1.071 min.

Example 153:(S)-1-(2-cyanobenzyl)-4-fluoro-N-(5-methyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepin-3-yl)-1H-pyrazole-3-carboxamide

2-(Bromomethyl) benzonitrile (39 mg, 0.20 mmol) was added to a stirringmixture of(S)-4-fluoro-N-(5-methyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepin-3-yl)-1H-pyrazole-3-carboxamide(50 mg, 0.16 mmol) and potassium carbonate (68 mg, 0.49 mmol) inN,N-dimethylformamide (4 mL). The resulting mixture was stirred at roomtemperature for 3 hours, diluted with water (5 mL) and extracted withethyl acetate (3×20 mL). The combined organic layers were washed withbrine, dried over anhydrous sodium sulfate, filtered and concentrated todry under vacuum. The residue was purified by Prep-HPLC with thefollowing conditions: Column: XBridge Prep C18 OBD Column 5 μm, 19×150mm; Mobile Phase A: water (10 mmol/L NH₄HCO₃), Mobile Phase B: ACN; Flowrate: 20 mL/min; Gradient: 25% B to 55% B over 7 min; 254 nm; Rt: 6.32min to afford the title compound. ¹H NMR (400 MHz, CD₃OD-d₄) δ 8.35 (dd,J=4.8, 1.6 Hz, 1H), 7.88 (d, J=4.5 Hz, 1H), 7.83 (dd, J=7.7, 1.3 Hz,1H), 7.73-7.66 (m, 2H), 7.56 (td, J=7.6, 1.1 Hz, 1H), 7.38 (d, J=7.9 Hz,1H), 7.32 (dd, J=8.0, 4.8 Hz, 1H), 5.59 (s, 2H), 5.01 (dd, J=11.5, 7.2Hz, 1H), 4.68 (dd, J=9.8, 7.2 Hz, 1H), 4.50 (dd, J=11.5, 9.9 Hz, 1H),3.49 (s, 3H). LC-MS (Method Q): m/z=421.3 [M+H]⁺, 1.201 min.

Example 154A and 154B:(R)-1-benzyl-N-(6,7-dihydroimidazo[1,2-d]pyrido[3,2-b][1,4]oxazepin-7-yl)-4-fluoro-1H-pyrazole-3-carboxamideand(S)-1-benzyl-N-(6,7-dihydroimidazo[1,2-d]pyrido[3,2-b][1,4]oxazepin-7-yl)-4-fluoro-1H-pyrazole-3-carboxamide

Step 1: Preparation of1-benzyl-N-(6,7-dihydroimidazo[1,2-d]pyrido[3,2-b][1,4]oxazepin-7-yl)-4-fluoro-1H-pyrazole-3-carboxamide

The crude product obtained using Amide Coupling Procedure C was purifiedby Prep-TLC (ethyl acetate/petroleum ether, 3/1) to afford the titlecompound (16 mg, 33.0%) as a white solid. LC-MS (Method S): m/z=405.2[M+H]⁺, 0.954 min.

Step 2: Preparation of(S)-1-benzyl-N-(6,7-dihydroimidazo[1,2-d]pyrido[3,2-b][1,4]oxazepin-7-yl)-4-fluoro-1H-pyrazole-3-carboxamide(First Eluting Isomer) and(R)-1-benzyl-N-(6,7-dihydroimidazo[1,2-d]pyrido[3,2-b][1,4]oxazepin-7-yl)-4-fluoro-1H-pyrazole-3-carboxamide(Second Eluting Isomer)

The racemate of1-benzyl-N-(6,7-dihydroimidazo[1,2-d]pyrido[3,2-b][1,4]oxazepin-7-yl)-4-fluoro-1H-pyrazole-3-carboxamide(16 mg, 0.039 mmol) was separated by Prep-Chiral-HPLC with the followingconditions: Column: CHIRALPAK IC, 5 μm, 2×25 cm; Mobile Phase A: hexane:DCM=5:1, Mobile Phase B: EtOH; Flow rate: 16 mL/min; Gradient: 50% B to50% B over 26 min; UV 254 & 220 nm; Rt 1: 3.96 min; Rt 2: 6.18 min toafford the title compounds:

Example 154A (first eluting isomer): ¹H NMR (300 MHz, Methanol-d₄) δ8.25-8.22 (m, 2H), 7.70 (d, J=4.5 Hz, 1H), 7.61 (dd, J=8.1, 1.5 Hz, 1H),7.34-7.22 (m, 6H), 7.07 (d, J=1.5 Hz, 1H), 5.73-5.69 (m, 1H), 5.25 (s,2H), 4.47-4.44 (m, 2H). LC-MS (Method T): m/z=405.2 [M+H]⁺, 1.063 min.

Example 154B (second eluting isomer): ¹H NMR (300 MHz, Methanol-d₄) δ8.25-8.22 (m, 2H), 7.70 (d, J=4.5 Hz, 1H), 7.61 (dd, J=8.1, 1.5 Hz, 1H),7.34-7.22 (m, 6H), 7.07 (d, J=1.5 Hz, 1H), 5.73-5.69 (m, 1H), 5.25 (s,2H), 4.47-4.44 (m, 2H). LC-MS (Method T): m/z=405.2 [M+H]⁺, 1.069 min.

Example 155:1-Benzyl-N-((2R,3S)-2,5-dimethyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepin-3-yl)-1H-pyrazole-3-carboxamide

Step 1: Preparation of 1-benzyl-1H-pyrazole-3-carboxylic acid

Sodium hydride (96 mg, 4 mmol) was added to a stirring mixture of ethyl1H-pyrazole-3-carboxylate (280 mg, 2 mmol) in N,N-dimethylformamide (20mL). The resulting mixture was stirred at room temperature for 2 hoursfollowed by the addition of (bromomethyl)benzene (340 mg, 2 mmol). Afterstirring for another 2 hours, the reaction mixture was diluted withwater (5 mL). Lithium hydroxide (96 mg, 4 mmol) was added and theresulting mixture was stirred overnight at room temperature, the pH wasadjusted to 6 with hydrochloric acid (2 N, 20 mL), and extracted withethyl acetate (3×20 mL). The combined organic layers were washed withbrine, dried over anhydrous sodium sulfate, filtered and concentratedunder vacuum. The residue was purified by Prep-HPLC with the followingconditions: Column: XBridge Shield RP18 OBD Column, 5 μm, 19×150 mm;Mobile Phase A: water (0.1% formic acid), Mobile Phase B: ACN; Flowrate: 20 mL/min; Gradient: 30% B to 55% B over 7 min; UV 254 & 220 nm;Rt: 4.9 min to afford the title compound (220 mg, 54.4%) as a whitesolid. LC-MS (Method E): m/z=202.9 [M+H]⁺, 0.855 min.

Step 2: Preparation of1-benzyl-N-((2R,3S)-2,5-dimethyl-4-oxo-2,3,4,5-tetrahydro-pyrido[3,2-b][1,4]oxazepin-3-yl)-1H-pyrazole-3-carboxamide

The crude product obtained using Amide Coupling Procedure C was purifiedby Prep-HPLC with the following conditions: Column: XBridge Shield RP18OBD Column, 5 μm, 19×150 mm; Mobile Phase A: water (0.1% formic acid),Mobile Phase B: ACN; Flow rate: 20 mL/min; Gradient: 25% B to 75% B over7 min; UV 254 & 220 nm; Rt: 3.3 min to afford the title compound. ¹H NMR(400 MHz, DMSO-d₆) δ 8.36 (dd, J=4.8, 1.6 Hz, 1H), 7.97 (d, J=2.0 Hz,1H), 7.76 (dd, J=8.0, 1.6 Hz, 1H), 7.70 (d, J=6.4 Hz, 1H), 7.42-7.25 (m,6H), 6.70 (d, J=2.0 Hz, 1H), 5.46 (s, 2H), 4.99-4.89 (m, 2H), 3.40 (s,3H), 1.32 (d, J=6.0 Hz, 3H). LC-MS (Method V): m/z=392.1 [M+H]⁺, 2.961min.

Example 156A and 156B:4-fluoro-1-(4-fluorobenzyl)-N-((1aR,2R,8bS)-4-methyl-3-oxo-1,1a,2,3,4,8b-hexahydrocyclopropa[d]pyrido[2,3-b]azepin-2-yl)-1H-pyrazole-3-carboxamideand4-fluoro-1-(4-fluorobenzyl)-N-((1aS,2S,8bR)-4-methyl-3-oxo-1,1a,2,3,4,8b-hexahydrocyclopropa[d]pyrido[2,3-b]azepin-2-yl)-1H-pyrazole-3-carboxamide

The crude product obtained using Amide Coupling Procedure C was purifiedby Prep-TLC (methanol/dichloromethane, 1/20) to afford the titlecompound as a white solid.

The racemate was separated by Prep-Chiral-HPLC with the followingconditions: Column: Chiralpak IC, 2×25 cm, 5 μm; Mobile Phase A: Hexane,Mobile Phase B: EtOH; Flow rate: 19 mL/min; Gradient: 35% B to 35% Bover 18.5 min; UV 220 & 254 nm; Rt1: 13.00; Rt2: 15.67 to afford thetitle compounds:

Example 156A (first eluting isomer): ¹H NMR (400 MHz, CD₃OD-d₄) δ 8.35(dd, J=4.8, 2.0 Hz, 1H), 7.92 (dd, J=7.6, 1.6 Hz, 1H), 7.77 (d, J=4.4Hz, 1H), 7.38-7.35 (m, 2H), 7.27 (dd, J=8.0, 4.8 Hz, 1H), 7.14-7.07 (m,2H), 5.31 (s, 2H), 4.63 (s, 1H), 3.39 (s, 3H), 2.28-2.22 (m, 1H),2.10-2.05 (m, 1H), 1.27-1.20 (m, 1H), 1.18-1.12 (m, 1H). LC-MS (MethodD): m/z=424.1 [M+H]⁺, 1.658 min.

Example 156B (second eluting isomer): ¹H NMR (400 MHz, CD₃OD-d₄) δ 8.35(dd, J=4.8, 2.0 Hz, 1H), 7.92 (dd, J=8.0, 2.0 Hz, 1H), 7.76 (d, J=4.4Hz, 1H), 7.49-7.35 (m, 2H), 7.26 (dd, J=7.6, 4.8 Hz, 1H), 7.12-7.08 (m,2H), 5.31 (s, 2H), 4.63 (s, 1H), 3.39 (s, 3H), 2.28-2.22 (m, 1H),2.10-2.04 (m, 1H), 1.26-1.19 (m, 1H), 1.18-1.27 (m, 1H). LC-MS (MethodD): m/z=424.1 [M+H]⁺, 1.664 min.

Example 157A and 157B:5-benzyl-N-((1aR,2R,8bS)-4-methyl-3-oxo-1,1a,2,3,4,8b-hexahydrocyclopropa[d]pyrido[2,3-b]azepin-2-yl)-1,3,4-oxadiazole-2-carboxamideand5-benzyl-N-((1aS,2S,8bR)-4-methyl-3-oxo-1,1a,2,3,4,8b-hexahydrocyclopropa[d]pyrido[2,3-b]azepin-2-yl)-1,3,4-oxadiazole-2-carboxamide

The crude product obtained using the procedure described in Example 54was purified by column chromatography (ethyl acetate/petroleum ether,1/1) to afford the title compound as a white solid.

The racemate was separated by Prep-Chiral-HPLC with the followingconditions: Column: CHIRALPAK AS-H, 2.0 cm I.D×25 cm, 5 μm; Mobile PhaseA: Hexane, Mobile Phase B: EtOH; Flow rate: 16 mL/min; Gradient: 50% Bto 50% B over 16 min; UV 220 & 254 nm; Rt1: 8.212; Rt2: 10.554 to affordthe title compounds:

Example 157A (first eluting isomer): ¹H NMR (300 MHz, DMSO-d₆) δ 9.48(d, J=6.6 Hz, 1H), 8.39 (dd, J=4.8, 1.8 Hz, 1H), 7.99 (dd, J=7.5, 1.8Hz, 1H), 7.37-7.27 (m, 6H), 4.42 (d, J=6.3 Hz, 1H), 4.38 (s, 2H), 3.34(s, 3H), 2.31-2.26 (m, 1H), 2.07-1.96 (m, 1H), 1.23-1.08 (m, 2H). LC-MS(Method X): m/z=390.1 [M+H]⁺, 2.745 min.

Example 157B (second eluting isomer): ¹H NMR (300 MHz, DMSO-d₆) δ 9.47(d, J=6.0 Hz, 1H), 8.39 (dd, J=6.6, 1.8 Hz, 1H), 7.97 (dd, J=7.5, 1.8Hz, 1H), 7.37-7.21 (m, 6H), 4.43 (d, J=6.3 Hz, 1H), 4.39 (s, 2H), 3.33(s, 3H), 2.32-2.26 (m, 1H), 2.03-1.99 (m, 1H), 1.23-1.08 (m, 2H). LC-MS(Method D): m/z=390.1 [M+H]⁺, 1.533 min.

Example 158:(S)-1-benzyl-5-cyano-N-(5-methyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepin-3-yl)-1H-pyrazole-3-carboxamide

Step 1: Preparation of ethyl 5-cyano-1H-pyrazole-3-carboxylate

Sodium nitrite (10.56 g, 153 mmol) was added to a mixture of ethylpropiolate (5.00 g, 51.1 mmol) and 2-aminoacetonitrile hydrochloride(9.44 g, 102 mmol) in chloroform (150 mL) and water (5 mL). The reactionmixture was stirred for 12 hours at room temperature, then heated to 60°C. and stirred for another 6 hours. After cooling to room temperature,the resulting mixture was filtered. The filtrate was washed with brine,dried over anhydrous sodium sulfate, filtered and concentrated undervacuum. The residue was purified by column chromatography (ethylacetate/petroleum ether, 1/9) to afford the title compound (2.90 g, 35%)as a yellow solid. LC-MS (Method C): m/z=166.1 [M+H]⁺, 1.032 min.

Step 2: Preparation of 5-cyano-1H-pyrazole-3-carboxylic acid

A solution of sodium hydroxide in water (2 M, 30 mL, 60 mmol) was addedto a mixture of ethyl 5-cyano-1H-pyrazole-3-carboxylate (1.5 g, 9.09mmol) in ethanol (25 mL). The reaction mixture was stirred for 4 hoursat room temperature. After removal of ethanol under reduced pressure,the pH value of the solution was adjusted to 3-4 with aqueoushydrochloric acid (1 M, 100 ml, 100 mmol). The resulting solution wasextracted with ethyl acetate (3×50 mL). The combined organic layers werewashed with brine, dried over anhydrous sodium sulfate, filtered andconcentrated under high vacuum to afford the title compound (400 mgcrude) as a yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ 14.89 (s, 1H),7.43 (s, 1H), 3.15 (s, 1H).

Step 3: Preparation of(S)-5-cyano-N-(5-methyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepin-3-yl)-1H-pyrazole-3-carboxamide

The crude product obtained using Amide Coupling Procedure C was purifiedby column chromatography (ethyl acetate/petroleum ether, 1/1) to affordthe title compound (180 mg, 53%) as a yellow solid. LC-MS (Method S):m/z=313.2[M+H]⁺, 0.749 min.

Step 4: Preparation of((S)-1-benzyl-5-cyano-N-(5-methyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepin-3-yl)-1H-pyrazole-3-carboxamide

Cesium carbonate (80 mg, 0.25 mmol) was added to a mixture of(S)-5-cyano-N-(5-methyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepin-3-yl)-1H-pyrazole-3-carboxamide(60 mg, 0.19 mmol) and (bromomethyl)benzene (39 mg, 0.23 mmol) inN,N-dimethylformamide (3 mL). The reaction mixture was stirred for 0.5hour at room temperature, diluted with water (50 mL) and extracted withethyl acetate (3×30 mL). The combined organic layers were washed withbrine, dried over anhydrous sodium sulfate, filtered and concentratedunder vacuum. The residue was purified by Prep-HPLC with the followingconditions: Column, XBridge Shield RP18 OBD, 5 μm, 19×150 mm; MobilePhase A: Water (0.1% formic acid); Mobile Phase B: MeCN; Flow rate: 20mL/min; Gradient: 20% B to 45% B over 7 min; UV 254 & 220 nm; Rt: 7 minto afford the title compound: ¹H NMR (400 MHz, DMSO-d₆) δ 8.67 (d, J=7.9Hz, 1H), 8.35 (dd, J=4.7, 1.6 Hz, 1H), 7.69 (dd, J=8.0, 1.6 Hz, 1H),7.58 (s, 1H), 7.44-7.29 (m, 4H), 7.28-7.22 (m, 2H), 5.65 (s, 2H),4.90-4.84 (m, 1H), 4.73-4.67 (m, 1H), 4.54-4.50 (m, 1H), 3.35 (s, 3H).LC-MS (Method T): m/z=403.2 [M+H]⁺, 1.412 min.

Example 159:(S)-5-cyano-1-(4-fluorobenzyl)-N-(5-methyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepin-3-yl)-1H-pyrazole-3-carboxamide

The crude product obtained using the procedure described in Example 158,Step 4 was purified by Prep-HPLC with the following conditions: Column:XBridge Shield RP18 OBD, 5 μm, 19×150 mm; Mobile Phase A: Water (10mmol/L NH₄HCO₃); Phase B: ACN; Flow rate: 20 mL/min; Gradient: 35% B to60% B over 12 min; UV 254 & 220 nm; Rt: 6.5 min to afford the titlecompound: ¹H NMR (400 MHz, DMSO-d₆) δ 8.67 (d, J=7.9 Hz, 1H), 8.36 (dd,J=4.8, 1.6 Hz, 1H), 7.70 (dd, J=7.9, 1.6 Hz, 1H), 7.59 (s, 1H),7.36-7.29 (m, 3H), 7.27-7.20 (m, 2H), 5.64 (s, 2H), 4.90-4.84 (m, 1H),4.72-4.67 (m, 1H), 4.54-4.50 (m, 1H), 3.36 (s, 3H). LC-MS (Method T):m/z=421.1 [M+H]⁺, 1.433 min.

Example 160A and 160B:(S)-5-benzyl-N-(5′-methyl-4′-oxo-4′,5′-dihydro-3′H-spiro[cyclopropane-1,2′-pyrido[3,2-b][1,4]oxazepin]-3′-yl)-1,3,4-oxadiazole-2-carboxamideand(R)-5-benzyl-N-(5′-methyl-4′-oxo-4′,5′-dihydro-3′H-spiro[cyclopropane-1,2′-pyrido[3,2-b][1,4]oxazepin]-3′-yl)-1,3,4-oxadiazole-2-carboxamide

Step 1: Preparation of ethyl 2-cyclopropylideneacetate

Ethyl 2-(triphenylphosphoranylidene)acetate (52 g, 149.42 mmol) wasadded to a mixture of (1-ethoxycyclopropoxy)trimethylsilane (20 g,114.94 mmol) and benzoic acid (1.83 g, 14.95 mmol) in toluene (150 mL).The reaction mixture was stirred at 80° C. overnight under nitrogenatmosphere. After cooling to room temperature, the reaction mixture wasconcentrated under reduced pressure. The residue was purified by columnchromatography (dichloromethane/petroleum ether, 1/1) to afford thetitle compound (2.1 g, 14%) as a colorless oil. LC-MS (Method S):m/z=127.2 [M+H]⁺, 0.886 min.

Step 2: Preparation of ethyl2-(1-((2-nitropyridin-3-yl)oxy)cyclopropyl)acetate

2-Nitropyridin-3-ol (3.36 g, 24.00 mmol) was added to a mixture of ethyl2-cyclopropylideneacetate (1.00 g, 7.93 mmol) and molecular sieves 4 Å(2.80 g) in dimethylacetamide (40 mL). The reaction mixture was stirredat 130° C. overnight under nitrogen atmosphere. After cooling to roomtemperature, the mixture was diluted with diethyl ether (150 mL) andwashed with aqueous sodium hydroxide (0.2 M, 3×200 mL). The combinedorganic layers were dried over anhydrous sodium sulfate, filtered andconcentrated under vacuum. The residue was purified by columnchromatography (dichloromethane/petroleum ether, 2/1) to afford thetitle compound (450 mg, 21%) as a yellow oil. LC-MS (Method S):m/z=267.2 [M+H]⁺, 0.935 min.

Step 3: Preparation of ethyl2-(1-((2-aminopyridin-3-yl)oxy)cyclopropyl)acetate

A mixture of ethyl 2-(1-((2-nitropyridin-3-yl)oxy)cyclopropyl)acetate(800 mg, 3.00 mmol) in methanol (30 mL) was hydrogenated in the presenceof palladium on carbon (10%, 80 mg) under hydrogen atmosphere (2-3 atm).The reaction mixture was stirred for 2 hours at room temperature. Themixture was filtered through Celite and the filtrate was concentratedunder high vacuum to afford the title compound (650 mg, 92%) as a yellowoil. LC-MS (Method S): m/z=237.1 [M+H]⁺, 0.587 min.

Step 4: Preparation of3′H-spiro[cyclopropane-1,2′-pyrido[3,2-b][1,4]oxazepin]-4′(5′H)-one

A solution of trimethylaluminum in toluene (2 M, 5.3 mL, 10.55 mmol) wasadded dropwise to a stirring mixture of ethyl2-(1-((2-aminopyridin-3-yl)oxy)cyclopropyl)acetate (500 mg, 2.11 mmol)in toluene (50 mL). The resulting mixture was stirred overnight at roomtemperature, quenched by the addition of water (50 mL) and extractedwith ethyl acetate (3×50 mL). The combined organic layers were washedwith brine, dried over anhydrous sodium sulfate, filtered andconcentrated under vacuum. The residue was purified by columnchromatography (ethyl acetate/petroleum ether, 1/3) to afford the titlecompound (290 mg, 72%) as a yellow oil. LC-MS (Method S): m/z=191.1[M+H]⁺, 0.704 min.

Step 5: Preparation of5′-methyl-3′H-spiro[cyclopropane-1,2′-pyrido[3,2-b][1,4]oxazepin]-4′(5′H)-one

Iodomethane (178 mg, 1.26 mmol) was added dropwise to a stirring mixtureof 3′H-spiro[cyclopropane-1,2′-pyrido[3,2-b][1,4]oxazepin]-4′(5′H)-one(200 mg, 1.05 mmol) and cesium carbonate (341 mg, 1.05 mmol) inN,N-dimethylformamide (10 mL). The reaction mixture was stirred for 2hours at 0° C., diluted with water (50 mL) and extracted with ethylacetate (3×50 mL). The combined organic layers were washed with brine,dried over anhydrous sodium sulfate, filtered and concentrated undervacuum. The residue was purified by column chromatography (ethylacetate/petroleum ether, 3/17) to afford the title compound (150 mg,69%) as a white solid. LC-MS (Method S): m/z=205.1 [M+H]⁺, 0.767 min.

Step 6: Preparation of3′-iodo-5′-methyl-3′H-spiro[cyclopropane-1,2′-pyrido[3,2-b][1,4]oxazepin]-4′(5′H)-one

N,N,N′,N′-tetramethylethylenediamine (0.49 g, 4.25 mmol) was added to amixture of5′-methyl-3′H-spiro[cyclopropane-1,2′-pyrido[3,2-b][1,4]oxazepin]-4′(5′H)-one(0.18 g, 0.85 mmol) in dichloromethane (40 mL) at 0° C. followed byaddition of iodotrimethylsilane (1.70 g, 8.50 mmol) dropwise over 20minutes. The mixture was stirred for 1 hour at 0° C. and then a solutionof iodine (0.32 g, 1.25 mmol) in dichloromethane (100 mL) was added tothe mixture. The reaction mixture was stirred for another 1 hour at 0°C., quenched by the addition of aqueous sodium thiosulfate (5%, 20 mL)and extracted with dichloromethane (3×50 mL). The combined organiclayers were washed with brine, dried over anhydrous sodium sulfate,filtered and concentrated under vacuum to afford the title compound (280mg crude) as a yellow oil. LC-MS (Method C): m/z=330.8 [M+H]⁺, 0.946min.

Step 7: Preparation of3′-azido-5′-methyl-3′H-spiro[cyclopropane-1,2′-pyrido[3,2-b][1,4]oxazepin]-4′(5′H)-one

Sodium azide (109 mg, 1.68 mmol) was added to a mixture of3′-iodo-5′-methyl-3′H-spiro[cyclopropane-1,2′-pyrido[3,2-b][1,4]oxazepin]-4′(5′H)-one(280 mg, 0.84 mmol) in N,N-dimethylformamide (5 mL). The resultingmixture was stirred for 2 hours at room temperature, quenched by theaddition of water (40 mL) and extracted with ethyl acetate (3×50 mL).The combined organic layers were washed with brine, dried over sodiumsulfate, filtered and concentrated under vacuum. The residue waspurified by Prep-TLC (ethyl acetate/petroleum ether, 1/2) to afford thetitle compound (70 mg, 33%) as a yellow solid. LC-MS (Method C):m/z=246.0 [M+H]⁺, 0.925 min.

Step 8: Preparation of3′-amino-5′-methyl-3′H-spiro[cyclopropane-1,2′-pyrido[3,2-b][1,4]oxazepin]-4′(5′H)-one

A mixture of3′-Azido-5′-methyl-3′H-spiro[cyclopropane-1,2′-pyrido[3,2-b][1,4]oxazepin]-4′(5′H)-one (70 mg, 0.28 mmol) in methanol (10 mL) was hydrogenatedin the presence of palladium on carbon (10%, 10 mg) under hydrogenatmosphere (2-3 atm). After stirring for 30 minutes at room temperaturethe reaction mixture was filtered through Celite and the filtrate wasconcentrated under vacuum to afford the title compound (50 mg, 78%) as awhite solid. LC-MS (Method S): m/z=220.2 [M+H]⁺, 0.690 min.

Step 9: Preparation of5-benzyl-N-(5′-methyl-4′-oxo-4′,5′-dihydro-3′H-spiro[cyclopropane-1,2′-pyrido[3,2-b][1,4]oxazepin]-3′-yl)-1,3,4-oxadiazole-2-carboxamide

The crude product obtained using the procedure described in Example 54was purified by Prep-TLC (ethyl acetate/petroleum ether, 1/1) to affordthe title compound (42 mg, 45%) as a white solid. LC-MS (Method S):m/z=406.0 [M+H]⁺, 1.024 min.

Step 10: Preparation of(S)-5-benzyl-N-(5′-methyl-4′-oxo-4′,5′-dihydro-3′H-spiro[cyclopropane-1,2′-pyrido[3,2-b][1,4]oxazepin]-3′-yl)-1,3,4-oxadiazole-2-carboxamideand(R)-5-benzyl-N-(5′-methyl-4′-oxo-4′,5′-dihydro-3′H-spiro[cyclopropane-1,2′-pyrido[3,2-b][,4]oxazepin]-3′-yl)-1,3,4-oxadiazole-2-carboxamide

The racemate of5-benzyl-N-(5′-methyl-4′-oxo-4′,5′-dihydro-3′H-spiro[cyclopropane-1,2′-pyrido[3,2-b][1,4]oxazepin]-3′-yl)-1,3,4-oxadiazole-2-carboxamide(42 mg, 0.10 mmol) was separated by Prep-Chiral-HPLC with the followingconditions: Column: CHIRALPAK IA, 2.12×15 cm, 5 μm; Mobile Phase A:Hexane, Mobile Phase B: IPA; Flow rate: 20 mL/min; Gradient: 50% B to50% B over 14 min; UV 254 & 220 nm; Rt 1: 12.359; Rt 2: 20.087 to affordthe title compounds:

Example 160A (first eluting isomer): ¹H NMR (300 MHz, DMSO-d₆) δ 9.01(d, J=8.7 Hz, 1H), 8.39 (dd, J=4.8, 1.5 Hz, 1H), 7.74 (dd, J=8.1, 1.5Hz, 1H), 7.39-7.27 (m, 6H), 5.20 (d, J=8.4 Hz, 1H), 4.35 (s, 2H), 3.40(s, 3H), 1.36-1.28 (m, 1H), 1.16-1.02 (m, 1H), 1.00-0.94 (m, 1H),0.58-0.50 (m, 1H). LC-MS (Method V): m/z=406.1 [M+H]⁺, 2.745 min.

Example 160B (second eluting isomer): ¹H NMR (300 MHz, DMSO-d₆) δ 9.01(d, J=8.4 Hz, 1H), 8.39 (dd, J=4.8, 1.5 Hz, 1H), 7.74 (dd, J=8.1, 1.5Hz, 1H), 7.39-7.27 (m, 6H), 5.20 (d, J=8.4 Hz, 1H), 4.35 (s, 2H), 3.40(s, 3H), 1.36-1.31 (m, 1H), 1.16-1.03 (m, 1H), 1.00-0.94 (m, 1H),0.58-0.50 (m, 1H). LC-MS (Method D): m/z=406.1 [M+H]⁺, 1.652 min.

Example 161:(S)-5-(3-cyanobenzyl)-N-(5-methyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepin-3-yl)-4H-1,2,4-triazole-3-carboxamide

Step 1: Preparation of methyl 2-(3-cyanophenyl)acetate

Sulfuric acid (98%, 2.0 mL) was added to a mixture of2-(3-cyanophenyl)acetic acid (3.5 g, 22.0 mmol) in methanol (80 mL). Theresulting mixture was stirred at room temperature for 3 hours andconcentrated under vacuum. The residue was diluted with water (40 mL)and extracted with ethyl acetate (3×60 mL). The combined organic layerswere washed with brine, dried over anhydrous sodium sulfate, filteredand concentrated under vacuum to afford the title compound (3.30 g, 87%)as a colorless oil. LC-MS (Method S): m/z=176.2 [M+H]⁺, 0.504 min.

Step 2: Preparation of 2-(3-cyanophenyl)acetohydrazide

Hydrazine hydrate (80%, 3.3 mL, 85.0 mmol) was added to a mixture ofmethyl 2-(3-cyanophenyl)acetate in methanol (50 mL). The reactionmixture was stirred at 65° C. overnight and then concentrated underreduced pressure. The residue was diluted with water (40 mL) andextracted with ethyl acetate (3×100 mL). The combined organic layerswere dried over anhydrous sodium sulfate, and filtered. The filtrate wasconcentrated under vacuum to afford the crude title compound (2.4 g,80%) as a white solid. LC-MS (Method S): m/z=176.2 [M+H]⁺, 0.506 min.

Step 3: Preparation of ethyl2-(2-(2-(3-cyanophenyl)acetyl)hydrazinyl)-2-iminoacetate

Ethyl 2-ethoxy-2-iminoacetate (1.82 g, 12.6 mmol) was added to astirring mixture of 2-(3-cyanophenyl)acetohydrazide (2.0 g, 11.5 mmol)in ethanol (20 mL) and diethyl ether (60 mL). The reaction mixture wasstirred at room temperature overnight. The white solid was collected byfiltration and rinsed with diethyl ether to afford the title compound(2.88 g, 92%) as a white solid. LC-MS (Method C): m/z=275.1 [M+H]⁺,0.913 min.

Step 4: Preparation of ethyl5-(3-cyanobenzyl)-4H-1,2,4-triazole-3-carboxylate

Molecular sieves 4 Å (50 mg) was added to a mixture of ethyl2-(2-(2-(3-cyanophenyl)-acetyl)hydrazinyl)-2-iminoacetate (1.0 g, 3.65mmol) in xylene (10 mL). The reaction mixture was stirred at 160° C.overnight in a sealed tube and concentrated under high vacuum. Theresidue was purified by column chromatography (ethyl acetate/petroleumether, 1/1) to afford the title compound (500 mg, 54%) as a white solid.LC-MS (Method S): m/z=257.2 [M+H]⁺, 0.767 min.

Step 5: Preparation of 5-(3-cyanobenzyl)-4H-1,2,4-triazole-3-carboxylicacid

A solution of lithium hydroxide (94 mg, 4.0 mmol) in water (5 mL) wasadded to a solution of ethyl5-(3-cyanobenzyl)-4H-1,2,4-triazole-3-carboxylate (500 mg, 2.0 mmol) intetrahydrofuran (15 mL). The resulting mixture was stirred at roomtemperature overnight. After removal of tetrahydrofuran under reducedpressure, the resulting solution was adjusted to pH=7 with aqueoushydrochloric acid (1 N, 10 mL) and extracted with ethyl acetate (3×20mL). The combined organic layers were washed with brine, dried overanhydrous sodium sulfate, filtered and concentrated under vacuum toafford the title compound (430 mg crude) as a white solid. LC-MS (MethodC): m/z=229.1 [M+H]⁺, 0.816 min.

Step 6: Preparation of(S)-5-(3-cyanobenzyl)-N-(5-methyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepin-3-yl)-4H-1,2,4-triazole-3-carboxamide

The crude product obtained using Amide Coupling Procedure C was purifiedby Prep-HPLC with the following conditions: Column: XBridge C18 OBD PrepColumn, 100 Å, 5 μm, 19 mm×250 mm; Mobile Phase A: Water (0.1% formicacid), Mobile Phase B: ACN; Flow rate: 20 mL/min; Gradient: 20% B to 45%B over 7 min; UV 254 & 220 nm; Rt: 7 min to afford the title compound:¹H NMR (400 MHz, DMSO-d₆) δ 14.53 (br s, 1H), 8.68 (s, 1H), 8.37 (dd,J=4.4, 1.2 Hz, 1H), 7.79-7.69 (m, 3H), 7.64-7.61 (m, 1H), 7.58-7.53 (m,1H), 7.36-7.32 (m, 1H), 4.90-4.82 (m, 1H), 4.75-4.69 (m, 1H), 4.55-4.49(m, 1H), 4.22 (s, 2H), 3.36 (s, 3H). LC-MS (Method T): m/z=404.2 [M+H]⁺,1.095 min.

Example 162:(S)-5-(3-cyano-5-fluorobenzyl)-N-(5-methyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepin-3-yl)-4H-1,2,4-triazole-3-carboxamide

Step 1: Preparation of methyl 2-(3-bromo-5-fluorophenyl)acetate

Thionyl chloride (4.26 g, 35.8 mmol) was added to a stirring mixture ofmethyl 2-(3-bromo-5-fluorophenyl)acetic acid (2.6 g, 11.93 mmol) inmethanol (30 mL) dropwise, followed by the addition ofN,N-dimethylformamide (two drops). The reaction mixture was stirred for2 hours at room temperature and concentrated under high vacuum. Theresidue was purified by column chromatography (ethyl acetate/petroleumether, 1/8) to afford the title compound (2.79 g, 92.2%) as a yellowsolid. LC-MS (Method S): m/z=247.1 [M+H]⁺, 1.079 min.

Step 2: Preparation of methyl 2-(3-cyano-5-fluorophenyl)acetate

Tetrakis(triphenylphosphanyl)palladium (1.2 g, 1.05 mmol) was added to amixture of methyl 2-(3-bromo-5-fluorophenyl)acetate (2.6 g, 10.5 mmol)and dicyanozinc (1.64 g, 14.17 mmol) in N,N-dimethylformamide (30 mL)under nitrogen atmosphere. The reaction mixture was heated at 140° C. bymicrowave and stirred for 3 hours. After cooling to room temperature,the reaction mixture was concentrated under vacuum. The residue waspurified by column chromatography (ethyl acetate/petroleum ether, 1/10)to afford the title compound (1.12 g, 54%) as a yellow solid. LC-MS(Method C): m/z=194 [M+H]⁺, 0.914 min.

Step 3: Preparation of 2-(3-cyano-5-fluorophenyl)acetohydrazide

Hydrazine hydrate (1.45 g, 29 mmol) was added to a mixture of methyl2-(3-cyano-5-fluorophenyl)acetate (1.12 g, 5.80 mmol) in methanol (20mL). The resulting mixture was heated at reflux, stirred for 3 hours andconcentrated under high vacuum. The residue was diluted with water (30mL) and extracted with ethyl acetate (3×20 mL). The combined organiclayers were washed with brine, dried over anhydrous sodium sulfate,filtered and concentrated under vacuum. The residue was purified bycolumn chromatography (ethyl acetate/petroleum ether, 3/1) to afford thetitle compound (0.92 g, 82.2%) as a white solid. LC-MS (Method S):m/z=194 [M+H]⁺, 0.30 min.

Step 4: Preparation of ethyl2-(2-(2-(3-cyano-5-fluorophenyl)acetyl)hydrazinyl)-2-iminoacetate

Ethyl 2-ethoxy-2-iminoacetate (692 mg, 4.77 mmol) was added to a stirredmixture of 2-(3-cyano-5-fluorophenyl)acetohydrazide (910 mg, 4.77 mmol)in ethanol (5 mL) and diethyl ether (15 mL). The reaction mixture wasstirred for 4 hours at room temperature. The solid was collected byfiltration and dried under high vacuum to afford the title compound (160mg, 80.8%) as a white solid. LC-MS (Method C): m/z=293 [M+H]⁺, 0.727min.

Step 5: Preparation of ethyl5-(3-cyano-5-fluorobenzyl)-4H-1,2,4-triazole-3-carboxylate

A mixture of ethyl2-(2-(2-(3-cyano-5-fluorophenyl)acetyl)hydrazinyl)-2-iminoacetate (1 g,3.42 mmol) and 4 Å molecular sieves in xylenes (20 mL) was stirred for 4hours at 160° C. After cooling to room temperature, the reaction mixturewas concentrated under high vacuum. The residue was purified by columnchromatography (ethyl acetate/petroleum ether, 1/1) to afford the titlecompound (0.75 g, 79.5%) as a white solid. LC-MS (Method C): m/z=275.0[M+H]⁺, 0.811 min.

Step 6: Preparation of5-(3-cyano-5-fluorobenzyl)-4H-1,2,4-triazole-3-carboxylic acid

Lithium hydroxide (79.2 mg, 3.3 mmol) was added to a stirring mixture ofethyl 5-(3-cyano-5-fluorobenzyl)-4H-1,2,4-triazole-3-carboxylate (140mg, 0.78 mmol) in tetrahydrofuran (10 mL) and water (3 mL). The reactionmixture was stirred overnight at room temperature. After removal oftetrahydrofuran under reduced pressure, the resulting solution wasadjusted to pH=6 with aqueous hydrochloric acid (1 M, 20 mL, 20 mmol),and extracted with ethyl acetate (3×30 mL). The combined organic layerswere washed with brine, dried over anhydrous sodium sulfate, filteredand concentrated under vacuum to afford the title compound (250 mgcrude) as a yellow solid. LC-MS (Method C): m/z=247.0 [M+H]⁺, 0.633 min.

Step 7. Preparation of(S)-5-(3-cyano-5-fluorobenzyl)-N-(5-methyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepin-3-yl)-4H-1,2,4-triazole-3-carboxamide

The crude product obtained using Amide Coupling Procedure C was purifiedby Prep-HPLC with the following conditions: Column: X bridge Prep C18,19×150 mm, 5 μm; Mobile phase: Phase A: water (10 mmol/L NH₄HCO₃); PhaseB: MeCN (20% to 80% over 12 min); Detector, UV 220 & 254 nm to affordthe title compound: ¹H NMR (300 MHz, DMSO-d₆) δ 14.37 (s, 1H), 8.56 (s,1H), 8.37 (dd, J=4.8, 1.5 Hz, 1H), 7.77-7.67 (m, 3H), 7.59-7.55 (m, 1H),7.33 (dd, J=8.1, 4.8 Hz, 1H), 4.91-4.71 (m, 2H), 4.45-4.48 (m, 1H), 4.26(s, 2H), 3.36 (s, 3H). LC-MS (Method D): m/z=422.1 [M+H]⁺, 1.367 min.

Example 163:(S)-5-(3-cyanobenzyl)-N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4H-1,2,4-triazole-3-carboxamide

The crude product obtained using Amide Coupling Procedure C was purifiedby Prep-HPLC with the following conditions: Column: SunFire Prep C18 OBDColumn 19×150 mm 5 μm 10 nm; Mobile Phase A: Water (10 mmol/L NH₄HCO₃),Mobile Phase B: ACN; Flow rate: 20 mL/min; Gradient: 25% B to 75% B in 7min; UV 254 & 220 nm; Rt: 6.34 min.: ¹H NMR (400 MHz, DMSO-d₆) δ 8.48(s, 1H), 7.78-7.73 (m, 2H), 7.64-7.61 (m, 1H), 7.57-7.49 (m, 2H),7.36-7.22 (m, 3H), 4.87-4.79 (m, 1H), 4.62-4.56 (m, 1H), 4.44-4.38 (m,1H), 4.20 (s, 2H), 3.32 (s, 3H). LCMS (Method D): m/z=403.1 [M+H]⁺,1.367 min.

Example 164:(S)-5-(3-cyanobenzyl)-N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)thiazole-2-carboxamide

Step 1: Preparation of ethyl 5-(bromomethyl)thiazole-2carboxylate

Benzoyl peroxide (6 mg, 0.02 mmol) was added to a mixture of ethyl5-methylthiazole-2-carboxylate (420 mg, 2.45 mmol) andN-bromosuccinimide (459 mg, 2.58 mmol) in carbon tetrachloride (6 mL).The resulting mixture was stirred overnight at 75° C. under nitrogenatmosphere, quenched by the addition of water (20 mL) and extracted withethyl acetate (3×20 mL). The combined organic layers were dried overanhydrous sodium sulfate, filtered and concentrated under vacuum. Theresidue was purified by column chromatography (ethyl acetate/petroleumether, 1/2) to afford the title compound (300 mg, 48.8%) as a yellowsolid. LC-MS (Method S): m/z=252.3 [M+H]⁺, 0.928 min.

Step 2: Preparation of 5-(3-cyanobenzyl)thiazole2-carboxylic acid

Tetrakis(triphenylphosphine)palladium (28 mg, 0.02 mmol) was added to amixture of ethyl 5-(bromomethyl)thiazole-2carboxylate (300 mg, 1.20mmol), (3-cyanophenyl)boronic acid (194 mg, 1.32 mmol) and potassiumcarbonate (190 mg, 1.37 mmol) in toluene/ethanol (5 mL/5 mL) undernitrogen atmosphere. The resulting mixture was stirred for 2 hours at90° C. After cooling to room temperature, the reaction mixture wasconcentrated under vacuum. The residue was diluted with water (30 mL),the pH value of the resulting solution was adjusted to 3 with aqueoushydrochloric acid (1 M, 50 mL, 50 mmol) and extracted with ethyl acetate(3×30 mL). The combined organic layers were washed with brine, driedover anhydrous sodium sulfate, filtered and concentrated under vacuum.The residue was purified by column chromatography(methanol/dichloromethane, 1/10) to afford the title compound (100 mg,34.1%) as a yellow oil. LC-MS (Method C): m/z=245.2 [M+H]⁺, 1.208 min.

Step 3: Preparation of(S)-5-(3-cyanobenzyl)-N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)thiazole-2-carboxamide

The crude product obtained using Amide Coupling Procedure B was purifiedby Prep-HPLC with the following conditions: Column: XBridge Shield RP18OBD Column, 5 μm, 19×150 mm; Mobile Phase A: Water (10 mmol/L NH₄HCO₃),Mobile Phase B: ACN; Flow rate: 20 mL/min; Gradient: 25% B to 65% B over7 min; UV 254 & 220 nm; Rt: 6.5 min to afford the title compound: ¹H NMR(300 MHz, DMSO-d₆) δ 8.82 (d, J=8.0 Hz, 1H), 7.93-7.90 (m, 1H),7.84-7.80 (m, 1H), 7.78-7.71 (m, 1H), 7.70-7.63 (m, 1H), 7.62-7.44 (m,2H), 7.40-7.20 (m, 3H), 4.88-4.75 (m, 1H), 4.73-4.60 (m, 1H), 4.48-4.37(m, 1H), 4.34 (s, 2H), 3.30 (s, 3H). LC-MS (Method V): m/z=419.2 [M+H]⁺,3.361 min.

Example 165:(S)-1-benzyl-5-fluoro-N-(5-methyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepin-3-yl)-1H-pyrazole-3-carboxamide

Step 1: Preparation of 5-fluoro-1H-pyrazole-3-carboxylic acid

A solution of sodium hydroxide (2 M, 0.63 mL, 1.26 mmol) was added to astirring mixture of ethyl 5-fluoro-1H-pyrazole-3-carboxylate (100 mg,0.63 mmol) in methanol (5 mL). The reaction mixture was stirred at roomtemperature overnight. After removal of methanol under reduced pressure,the resulting solution was adjusted to pH=5 with aqueous hydrochloricacid (1 N, 2 mL) and extracted with ethyl acetate (3×30 mL). Thecombined organic layers were washed with brine, dried over anhydroussodium sulfate, and filtered. The filtrate was concentrated under vacuumto afford the title compound (80 mg, 97%) as a white solid. ¹H NMR (300MHz, DMSO-d₆) δ 13.67 (s, 1H), 613.49 (s, 1H), δ 6.47 (dd, J=6.3, 2.2Hz, 1H).

Step 2: Preparation of(S)-5-fluoro-N-(5-methyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepin-3-yl)-1H-pyrazole-3-carboxamide

The crude product obtained using Amide Coupling Procedure C was purifiedby column chromatography (methanol/dichloromethane, 1/10) to afford thetitle compound (100 mg, 56.8%) as a white solid. LC-MS (Method E):m/z=306.1 [M+H]⁺, 0.898 min.

Step 3: Preparation of(S)-1-benzyl-5-fluoro-N-(5-methyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepin-3-yl)-1H-pyrazole-3-carboxamide

The crude product obtained using the procedure described in Example 158,Step 4 was purified by Prep-HPLC with the following conditions: Column,XBridge Prep C18 OBD Column, 5 μm, 19×150 mm; Mobile phase: Phase A:Water (0.05% TFA), Phase B: MeCN; Flow rate: 20 mL/min; Gradient: 25% Bto 55% B in 7 min; Detector, UV 254 & 220 nm to afford the titlecompound: ¹H NMR (300 MHz, CD₃OD-d₄) δ 8.30 (dd, J=4.7, 1.6 Hz, 1H),7.63 (dd, J=8.0, 1.6 Hz, 1H), 7.40-7.20 (m, 6H), 6.27 (d, J=5.6 Hz, 1H),5.30 (s, 2H), 4.96 (dd, J=11.6, 7.2 Hz, 1H), 4.62 (dd, J=9.8, 7.2 Hz,1H), 4.46 (dd, J=11.6, 9.8 Hz, 1H), 3.44 (s, 3H). LC-MS (Method D):m/z=396.1 [M+H]⁺, 1.659 min.

Example 166:(S)-5-fluoro-1-(4-fluorobenzyl)-N-(5-methyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepin-3-yl)-1H-pyrazole-3-carboxamide

The crude product obtained using the procedure described in Example 158,Step 4 was purified by Prep-HPLC with the following conditions: Column,XBridge Prep C18 OBD Column, 5 μm, 19×150 mm; Mobile Phase A: Water(0.05% TFA), Mobile Phase B: MeCN; Flow rate: 20 mL/min; Gradient: 5% Bto 55% B over 7 min; Detector, UV 254 & 220 nm to afford the titlecompound: ¹H NMR (300 MHz, CD₃OD-d₄) δ 8.30 (dd, J=4.8, 1.6 Hz, 1H),7.63 (dd, J=8.0, 1.6 Hz, 1H), 7.33-7.25 (m, 3H), 7.14-7.01 (m, 2H), 6.27(d, J=5.6 Hz, 1H), 5.29 (s, 2H), 4.96 (dd, J=11.5, 7.2 Hz, 1H), 4.62(dd, J=9.8, 7.2 Hz, 1H), 4.46 (dd, J=11.5, 9.8 Hz, 1H), 3.44 (s, 3H).LC-MS (Method D): m/z=414.1 [M+H]⁺, 1.667 min.

Example 167:(S)-5-cyano-1-(3-cyanobenzyl)-N-(5-methyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepin-3-yl)-1H-pyrazole-3-carboxamide

The crude product obtained using the procedure described in Example 158,Step 4 was purified by Prep-HPLC with the following conditions: Column:XBridge Shield RP18 OBD, 5 μm, 19×150 mm; Mobile Phase A: Water (10mmol/L NH₄HCO₃); Mobile Phase B: MeCN; Flow rate: 20 mL/min; Gradient:25% B to 55% B over 7 min; UV 254 & 220 nm; Rt: 6.32 min to afford thetitle compound: ¹H NMR (400 MHz, DMSO-d₆) δ 8.67 (d, J=7.9 Hz, 1H), 8.36(dd, J=4.7, 1.6 Hz, 1H), 7.87-7.82 (m, 1H), 7.80-7.75 (m, 1H), 7.69 (dd,J=8.0, 1.6 Hz, 1H), 7.65-7.58 (m, 2H), 7.52-7.58 (m, 1H), 7.35-7.28 (m,1H), 5.73 (s, 2H), 4.90-4.81 (m, 1H), 4.72-4.63 (m, 1H), 4.54-4.47 (m,1H), 3.35 (s, 3H). LC-MS (Method T): m/z=428.1 [M+H]⁺, 1.320 min.

Example 168:(S)-1-((5-cyanopyridin-3-yl)methyl)-4-fluoro-N-(5-methyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepin-3-yl)-1H-pyrazole-3-carboxamide

5-(Bromomethyl)nicotinonitrile (35 mg, 0.18 mmol) was added into astirring mixture of(S)-4-fluoro-N-(5-methyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepin-3-yl)-1H-pyrazole-3-carboxamide(45 mg, 0.15 mmol) and potassium carbonate (62 mg, 0.45 mmol) inN,N-dimethylformamide (4 mL). The resulting mixture was stirred at roomtemperature for 3 hours, diluted with water (20 mL) and extracted withethyl acetate (3×20 mL). The combined organic layers were washed withbrine, dried over anhydrous sodium sulfate, filtered and concentratedunder vacuum. The crude product obtained using the procedure describedin Example 158, Step 4 was purified by Prep-HPLC with the followingconditions: Column: XBridge Shield RP18 OBD Column, 5 μm, 19×150 mm;Mobile Phase A: Water (10 mmol/L NH₄HCO₃), Mobile Phase B: ACN; Flowrate: 20 mL/min; Gradient: 35% B to 50% B over 7 min; UV 254 & 220 nm;Rt: 6.5 min to afford the title compound: ¹H NMR (400 MHz, CD₃OD-d₄) δ8.91 (d, J=1.9 Hz, 1H), 8.82 (d, J=2.1 Hz, 1H), 8.35 (dd, J=4.8, 1.6 Hz,1H), 8.19 (t, J=2.0 Hz, 1H), 7.92 (d, J=4.4 Hz, 1H), 7.68 (dd, J=8.0,1.6 Hz, 1H), 7.32 (dd, J=8.0, 4.8 Hz, 1H), 5.48 (s, 2H), 5.02 (dd,J=11.5, 7.2 Hz, 1H), 4.69 (dd, J=9.9, 7.2 Hz, 1H), 4.51 (dd, J=11.5, 9.9Hz, 1H), 3.50 (s, 3H). LC-MS (Method D): m/z=422.0 [M+H]⁺, 1.328 min.

Example 169:(S)-5-benzyl-N-(5-trideuteriomethyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepin-3-yl)-4H-1,2,4-triazole-3-carboxamide

Step 1: Preparation of (S)-tert-butyl(5-trideuteriomethyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepin-3-yl)carbamate

Trideuterated iodomethane (233.5 mg, 1.61 mmol) was added to a stirringmixture of (S)-tert-butyl4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepin-3-ylcarbamate (450mg, 1.61 mmol) and cesium carbonate (629.2 mg, 1.93 mmol) inN,N-dimethylformamide (10 mL) at 0° C. The reaction mixture was stirredat 0° C. for 2 hours, diluted with water (20 mL) and extracted withethyl acetate (3×20 mL). The combined organic layers were washed withbrine, dried over anhydrous sodium sulfate and concentrated under vacuumto afford the title compound (360 mg, 75.5%) as a white solid. LC-MS(Method E): m/z=297.2 [M+H]⁺, 0.903 min.

Step 2: Preparation of(S)-3-amino-5-trideuteriomethyl-2,3-dihydropyrido[3,2-b][1,4]oxazepin-4(5H)-onehydrochloride

(S)-tert-butyl(5-trideuteriomethyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepin-3-yl)carbamate(200 mg, 0.68 mmol) was added to a solution of hydrochloride in1,4-dioxane (4 M, 5 mL, 20 mmol). The reaction mixture was stirred atroom temperature for 2 hours and concentrated under vacuum to afford thetitle compound (140 mg crude) as a white solid. LC-MS (Method E):m/z=197.1 [M+H]⁺, 0.761 min.

Step 3: Preparation of(S)-5-benzyl-N-(5-trideuteriomethyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepin-3-yl)-4H-1,2,4-triazole-3-carboxamide

The crude product obtained using Amide Coupling Procedure C was purifiedby Prep-HPLC with the following conditions: Column, XBridge Prep C18 OBDColumn, 5 μm, 19×150 mm; Mobile Phase A: Water (10 mmol/L NH₄CO₃),Mobile Phase B: MeCN; Flow rate: 20 mL/min; Gradient: 25% B to 50% Bover 7 min; Detector, UV 254 & 220 nm to afford the title compound: ¹HNMR (400 MHz, CD₃OD-d₄) δ 8.33 (dd, J=4.8, 1.6 Hz, 1H), 7.66 (dd, J=8.0,1.6 Hz, 1H), 7.38-7.22 (m, 6H), 5.02 (dd, J=11.6, 7.2 Hz, 1H), 4.67 (dd,J=9.9, 7.2 Hz, 1H), 4.51 (dd, J=11.5, 9.9 Hz, 1H), 4.16 (s, 2H). LC-MS(Method D): m/z=382.1 [M+H]⁺, 1.371 min.

Example 170A and 170B:1-(3-cyanobenzyl)-N-((1aS,2S,8bR)-5,7-difluoro-3-oxo-1,1a,2,3,4,8b-hexahydrobenzo[b]cyclopropa[d]azepin-2-yl)-4-fluoro-1H-pyrazole-3-carboxamideand1-(3-cyanobenzyl)-N-((1aR,2R,8bS)-5,7-difluoro-3-oxo-1,1a,2,3,4,8b-hexahydrobenzo[b]cyclopropa[d]azepin-2-yl)-4-fluoro-1H-pyrazole-3-carboxamide

The crude product obtained using Amide Coupling Procedure C was purifiedby Prep-TLC (ethyl acetate/petroleum ether, 3/1) to afford the titlecompound as a white solid.

The racemate was separated by Prep-Chiral-HPLC with the followingconditions: Column: (R,R)WHELK-015/100 Kromasil, 2.11 cm×25 cm (5 μm);Mobile Phase A: Hexane, Mobile Phase B: EtOH; Flow rate: 20 mL/min;Gradient: 60% B to 60% B over 22 min; UV 254 & 220 nm; Rt1: 14.06; Rt2:18.79 to afford the title compounds:

Example 170A (first eluting isomer): ¹H NMR (400 MHz, CD₃OD-d₄) δ 7.88(d, J=4.4, Hz, 1H), 7.75-7.72 (m, 2H), 7.66-7.63 (m, 1H), 7.61-7.56 (m,1H), 7.13-7.09 (m, 1H), 6.99-6.92 (m, 1H), 5.23 (s, 2H), 4.82 (s, 1H),2.31-2.24 (m, 1H), 2.15-2.09 (m, 1H), 1.66-1.61 (m, 1H), 1.22-1.17 (m,1H). LC-MS (Method D): m/z=452.1 [M+H]⁺, 1.627 min.

Example 170B (second eluting isomer): ¹H NMR (400 MHz, CD₃OD-d₄) δ 7.88(d, J=4.4 Hz, 1H), 7.74-7.72 (m, 2H), 7.67-7.63 (m, 1H), 7.61-7.56 (m,1H), 7.13-7.09 (m, 1H), 6.99-6.92 (m, 1H), 5.43 (s, 2H), 4.82 (s, 1H),2.29-2.25 (m, 1H), 2.15-2.11 (m, 1H), 1.66-1.60 (m, 1H), 1.22-1.15 (m,1H). LC-MS (Method V): m/z=452.1 [M+H]⁺, 2.781 min.

Example 171:(S)-1-(3-cyanobenzyl)-N-(5-methyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide

Step 1: Preparation of methyl1-(3-cyanobenzyl)-1H-1,2,4-triazole-3-carboxylate

Sodium hydride (60%, 0.38 g, 9.5 mmol) was added to a stirring mixtureof methyl 1H-1,2,4-triazole-3-carboxylate (1.0 g, 7.87 mmol) inN,N-dimethylformamide (20 mL). The resulting mixture was stirred for 1hour at room temperature, followed by the addition of3-(bromomethyl)benzonitrile (1.69 g, 8.67 mmol). The resulting mixturewas stirred for another 1 hour at room temperature, diluted with water(30 mL) and extracted with dichloromethane (3×50 mL). The combinedorganic layers were washed with brine, dried over anhydrous sodiumsulfate, filtered and concentrated under vacuum. The residue waspurified by column chromatography (ethyl acetate/petroleum ether, 1/4)to afford the title compound (600 mg, 31.5%) as a white solid. LC-MS(Method C): m/z=243.1 [M+H]⁺, 0.925 min.

Step 2: Preparation of 1-(3-cyanobenzyl)-1H-1,2,4-triazole-3-carboxylicacid

A solution of lithium hydroxide (360 mg, 15.0 mmol) in water (10 ml) wasadded to a stirring mixture of1-(3-cyanobenzyl)-1H-1,2,4-triazole-3-carboxylate (600 mg, 2.48 mmol) intetrahydrofuran (20 ml). The reaction mixture was stirred at roomtemperature for 2 hours. After removal of tetrahydrofuran under reducedpressure, the resulting solution was adjusted to pH=7 with aqueoushydrochloric acid (1 N, 10 mL), and extracted with ethyl acetate (3×50mL). The combined organic layers were washed with brine, dried overanhydrous sodium sulfate, filtered and concentrated under vacuum toafford the title compound (250 mg, 17.7%) as a white solid. LC-MS(Method X): m/z=229.1 [M+H]⁺, 1.227 min.

Step 3: Preparation of(S)-1-(3-cyanobenzyl)-N-(5-methyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide

The crude product obtained using Amide Coupling Procedure C was purifiedby Prep-HPLC with the following conditions: Column: XBridge Prep C18 OBDColumn 19×150 mm 5 μm; Mobile Phase A: Water (10 mmol/L NH₄HCO₃), MobilePhase B: MeCN; Flow rate: 20 mL/min; Gradient: 20% B to 45% B over 7min; 254 nm; Rt: 6 min to afford the title compound: ¹H NMR (400 MHz,CD₃OD-d₄) δ 8.64 (s, 1H), 8.33 (dd, J=4.8, 1.6 Hz, 1H), 7.77-7.64 (m,4H), 7.57 (t, J=7.7 Hz, 1H), 7.30 (dd, J=8.0, 4.8 Hz, 1H), 5.55 (s, 2H),5.03 (dd, J=11.7, 7.3 Hz, 1H), 4.69 (dd, J=9.9, 7.1 Hz, 1H), 4.52 (dd,J=11.2, 9.6 Hz, 1H), 3.47 (s, 3H). LC-MS (Method D): m/z=404.2 [M+H]⁺,1.371 min.

Example 172:1-(3-cyanobenzyl)-N-((2R,3S)-2,5-dimethyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide

The crude product obtained using Amide Coupling Procedure C was purifiedby Prep-HPLC with the following conditions: Column: XBridge Prep C18 OBDColumn, 5 μm, 19×150 mm; Mobile Phase A: Water (10 mmol/L NH₄HCO₃),Mobile Phase B: MeCN; Flow rate: 20 mL/min; Gradient: 25% B to 75% Bover 7 min; 254 nm; Rt: 6.25 min to afford the title compound: ¹H NMR(300 MHz, CD₃OD-d₄) δ 8.66 (s, 1H), 8.33 (dd, J=4.8, 1.6 Hz, 1H),7.78-7.65 (m, 4H), 7.57 (t, J=7.8 Hz, 1H), 7.32 (dd, J=8.0, 4.8 Hz, 1H),5.56 (s, 2H), 5.07-5.01 (m, 2H), 3.49 (s, 3H), 1.38 (d, J=5.9 Hz, 3H).LC-MS (Method D): m/z=418.2 [M+H]⁺, 1.477 min.

Example 173:(S)—N-(5-trideuteriomethyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepin-3-yl)-5-(1-phenylcyclopropyl)-1,3,4-oxadiazole-2-carboxamide

The crude product obtained using the procedure described in Example 54was purified by Prep-HPLC with the following conditions: Column, XBridgePrep C18 OBD Column, 5 μm, 19×150 mm; Mobile phase: Phase A: Water (10mmol/L NH₄HCO₃), Phase B: MeCN; Flow rate: 20 mL/min; Gradient: 25% B to50% B over 7 min; Detector, UV 254 nm to afford the title compound: ¹HNMR (300 MHz, DMSO-d₆) δ 9.49 (d, J=7.6 Hz, 1H), 8.36 (dd, J=4.7, 1.6Hz, 1H), 7.70 (dd, J=8.0, 1.6 Hz, 1H), 7.50-7.28 (m, 6H), 4.87-4.62 (m,2H), 4.50 (dd, J=9.3, 7.1 Hz, 1H), 1.72-1.62 (m, 2H), 1.55-1.44 (m, 2H).LC-MS (Method D): m/z=409.1 [M+H]⁺, 1.624 min.

Example174:5-benzyl-N-((2R,3S)-2-methyl-5-trideuteriomethyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepin-3-yl)-1,3,4-oxadiazole-2-carboxamide

Step 1: Preparation of tert-butyl((2R,3S)-2-methyl-5-trideuteriomethyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepin-3-yl)carbamate

Trideuterated iodomethane (124 mg, 0.85 mmol) was added to a stirringmixture of tert-butyl(2R,3S)-2-methyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepin-3-ylcarbamate(250 mg, 0.85 mmol) and cesium carbonate (278 mg, 0.85 mmol) inN,N-dimethylformamide (30 mL). The reaction mixture was stirred at roomtemperature for 5 hours, diluted with water (20 mL) and extracted withethyl acetate (3×100 mL). The organic layers were combined, dried overanhydrous sodium sulfate, filtered and concentrated under vacuum. Theresidue was purified by column chromatography (methanol/dichloromethane,1/20) to afford the title compound (230 mg, 87.1%) as a white solid.LC-MS (Method C): m/z=311.1 [M+H]⁺, 1.260 min.

Step 2: Preparation of (2R,3S)-3-amino-2-imethyl-5-trideuteratedmethyl-2,3-dihydropyrido[3,2-b][1,4]oxazepin-4(5H)-one hydrochloride

Tert-butyl((2R,3S)-2-methyl-5-trideuteriomethyl-4-oxo-2,3,4,5tetrahydropyrido[3,2-b][1,4]oxazepin-3-yl)carbamate(100 mg, 0.32 mmol) was added to a solution of hydrogen chloride in1.4-dioxane (4 N, 6.0 mL, 24 mmol). The reaction mixture was stirred atroom temperature for 3 hours and concentrated under vacuum to afford thetitle compound (80 mg, 99%) as a white solid. LC-MS (Method C):m/z=211.1 [M+H]⁺, 0.757 min.

Step 3: Preparation of5-benzyl-N-((2R,3S)-2-methyl-5-trideuteriomethyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepin-3-yl)-1,3,4-oxadiazole-2-carboxamide

The crude product obtained using the procedure described in Example 54was purified by Prep-HPLC with the following conditions: Column: XBridgePrep OBD C18 Column 19×250 mm, 5 μm; Mobile Phase A: Water (10 mmol/LNH₄HCO₃), Mobile Phase B: MeCN; Flow rate: 20 mL/min; Gradient: 25% B to75% B over 7 min; UV 254 & 220 nm; Rt: 6.85 min to afford the titlecompound: ¹H NMR (400 MHz, DMSO-d₆) δ 8.58 (s, 1H), 8.36 (dd, J=4.8, 1.6Hz, 1H), 7.74 (dd, J=8.0, 1.6 Hz, 1H), 7.40-7.28 (m, 6H), 4.98-4.90 (m,2H), 4.38 (s, 2H), 1.37 (d, J=6.4 Hz, 3H). LC-MS (Method D): m/z=397.2[M+H]⁺, 1.680 min.

Example 175:(S)-1-benzyl-4-fluoro-N-(5-trideuteriomethyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepin-3-yl)-1H-pyrazole-3-carboxamide

The crude product obtained using Amide Coupling Procedure C was purifiedby Prep-HPLC with the following conditions: Column, XBridge Prep C18 OBDColumn, 5 μm, 19×150 mm; Mobile phase: Phase A: Water (10 mmol/LNH₄HCO₃), Phase B: MeCN; Flow rate: 20 mL/min; Gradient: 25% B to 65% Bover 7 min; Detector, UV 254 nm to afford the title compound: ¹H NMR(300 MHz, DMSO-d₆) δ 8.32 (dd, J=4.7, 1.6 Hz, 1H), 8.21 (d, J=7.8 Hz,1H), 8.10 (d, J=4.5 Hz, 1H), 7.66 (dd, J=8.0, 1.6 Hz, 1H), 7.42-7.19 (m,6H), 5.31 (s, 2H), 4.85-4.76 (m, 1H), 4.64 (dd, J=11.5, 9.7 Hz, 1H),4.47 (dd, J=9.6, 7.4 Hz, 1H). LC-MS (Method J): m/z=399.3 [M+H]⁺, 1.331min.

Example176:5-benzyl-N-((1aR,2S,8bS)-5,7-difluoro-3-oxo-1,1a,2,3,4,8b-hexahydrobenzo[b]cyclopropa[d]azepin-2-yl)-4H-1,2,4-triazole-3-carboxamide

The crude product obtained using Amide Coupling Procedure C was purifiedby Prep-HPLC with the following conditions: Column: Column: XBridge PrepOBD C18 Column 30×150 mm 5 μm; Mobile Phase A: Water (10 mmol/LNH₄HCO₃), Mobile Phase B: MeCN; Flow rate: 60 mL/min; Gradient: 25% B to55% B over 7 min; 254 nm; Rt: 6.32 min to afford the title compound: ¹HNMR (400 MHz, DMSO-d₆) δ 14.34 (br s, 1H), 9.72 (s, 1H), 8.62 (s, 1H),7.35-7.18 (m, 7H), 4.12 (s, 2H), 3.98 (dd, J=10.5, 7.5 Hz, 1H),2.26-2.17 (m, 1H), 1.87-1.77 (m, 1H), 1.13-1.04 (m, 1H), 0.60-0.57 (m,1H). LC-MS (Method Q): m/z=410.5 [M+H]⁺, 1.773 min.

Example 177A and 177B:5-benzyl-N-((7S,7aS,8aR)-5-methyl-6-oxo-5,6,7,7a,8,8a-hexahydrocyclopropa[d]pyrazino[2,3-b]azepin-7-yl)-1,3,4-oxadiazole-2-carboxamideand5-benzyl-N-((7R,7aR,8aS)-5-methyl-6-oxo-5,6,7,7a,8,8a-hexahydrocyclopropa[d]pyrazino[2,3-b]azepin-7-yl)-1,3,4-oxadiazole-2-carboxamide

The crude product obtained using the procedure described in Example 54was purified by Prep-TLC (ethyl acetate/petroleum ether, 3/1) to affordthe title compound as a white solid.

The racemate of5-benzyl-N-(cis-5-methyl-6-oxo-5,6,7,7a,8,8a-hexahydrocyclopropa[d]pyrazino[2,3-b]azepin-7-yl)-1,3,4-oxadiazole-2-carboxamide (40 mg,0.10 mmol) was separated by Prep-Chiral-HPLC with the followingconditions: Column: CHIRAL ART Cellulose-SB S-5 μm, 250×20 mm, 5 μm;Mobile Phase A: Hexane, Mobile Phase B: EtOH; Flow rate: 20 mL/min;Gradient: 50% B to 50% B over 26 min; 220/254 nm; Rt1: 19.32; Rt 2:23.55 to afford the title compounds:

Example 177A (first eluting isomer): ¹H NMR (400 MHz, CD₃OD-d₄) δ8.42-8.37 (m, 2H), 7.37-7.25 (m, 5H), 4.77 (s, 1H), 4.33 (s, 2H), 3.40(s, 3H), 2.65-2.57 (m, 1H), 2.25-2.17 (m, 1H), 1.55-1.48 (m, 1H),1.35-1.30 (m, 1H). LCMS (Method D): m/z=391.1 [M+H]⁺, 1.231 min.

Example 177B (second eluting isomer): ¹H NMR (400 MHz, CD₃OD-d₄) δ8.42-8.37 (m, 2H), 7.36-7.25 (m, 5H), 4.77 (s, 1H), 4.33 (s, 2H), 3.39(s, 3H), 2.64-2.56 (m, 1H), 2.24-2.16 (m, 1H), 1.54-1.46 (m, 1H),1.34-1.28 (m, 1H). LC-MS (Method D): m/z=391.1 [M+H]⁺, 1.225 min.

Example 178A and 178B:(S)-4-fluoro-1-(2-fluorobenzyl)-N-(5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrazino[2,3-b]azepin-7-yl)-1H-pyrazole-3-carboxamideand(R)-4-fluoro-1-(2-fluorobenzyl)-N-(5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrazino[2,3-b]azepin-7-yl)-1H-pyrazole-3-carboxamide

Step 1: Preparation of ethyl 4-(3-aminopyrazin-2-yl)butanoate

A solution of (4-ethoxy-4-oxobutyl)zinc(II) bromide in tetrahydrofuran(0.5 M, 26.0 mL, 13.0 mmol) was added to a mixture of3-bromopyrazin-2-amine (1.0 g, 5.8 mmol) andtetrakis(triphenylphosphanyl)palladium (0.67 g, 0.58 mmol) intetrahydrofuran (60 mL) under a nitrogen atmosphere. The resultingmixture was stirred overnight at 70° C. After cooling to roomtemperature, the reaction mixture was concentrated under reducedpressure. The resulting residue was purified by column chromatography(methanol/dichloromethane, 1/10) to afford the title compound (0.45 g,37.0%) as a light yellow oil. LC-MS (Method S): m/z=210.2 [M+H]⁺, 0.592min.

Step 2: Preparation of 8,9-dihydro-5H-pyrazino[2,3-b]azepin-6(7H)-one

A solution of trimethylaluminum in toluene (2 M, 6.0 mL, 12.0 mmol) wasadded to a stirring mixture of ethyl 4-(3-aminopyrazin-2-yl)butanoate(450 mg, 2.2 mmol) in toluene (20 mL). After stirring overnight at roomtemperature, the reaction mixture was quenched by the addition of water(50 mL) and extracted with dichloromethane (3×50 mL). The combinedorganic layers were washed with brine, dried over anhydrous sodiumsulfate, filtered and concentrated under reduced pressure. The resultingresidue was purified by column chromatography (methanol/dichloromethane,1/10) to afford the title compound (0.32 g, 91.0%) as a light yellowsolid. LC-MS (Method S): m/z=164.2 [M+H]⁺, 0.473 min.

Step 3: Preparation of5-methyl-8,9-dihydro-5H-pyrazino[2,3-b]azepin-6(7H)-one

Iodomethane (313 mg, 2.2 mmol) was added dropwise to a stirring mixtureof 8,9-dihydro-5H-pyrazino[2,3-b]azepin-6(7H)-one (320 mg, 2.0 mmol) andcesium carbonate (717 mg, 2.2 mmol) in N,N-dimethylformamide (15 mL).After stirring overnight at room temperature, the reaction mixture wasdiluted with water (20 mL) and extracted with ethyl acetate (3×50 mL).The combined organic layers were washed with brine, dried over anhydroussodium sulfate, filtered and concentrated under reduced pressure. Theresulting residue was purified by column chromatography(methanol/dichloromethane, 1/10) to afford the title compound (300 mg,87.0%) as a light yellow solid. LC-MS (Method S): m/z=178.1 [M+H]⁺,0.570 min.

Step 4: Preparation of7-iodo-5-methyl-8,9-dihydro-5H-pyrazino[2,3-b]azepin-6(7H)-one

To a mixture of 5-methyl-8,9-dihydro-5H-pyrazino[2,3-b]azepin-6(7H)-one(300 mg, 1.70 mmol) and N,N,N′,N′-tetramethylethylenediamine (1.97 g,17.0 mmol) in dichloromethane (80 mL) at 0° C. was addediodotrimethylsilane (2.38 g, 17.0 mmol) dropwise over 30 minutes. Theresulting mixture was stirred for 2 hours at 0° C., followed by theaddition of a solution of iodine (0.65 g, 2.6 mmol) in dichloromethane(100 mL) dropwise over 30 minutes. After stirring for 1 hour at roomtemperature, the reaction mixture was quenched by the addition ofaqueous sodium thiosulfate (5%, 20 mL) and extracted with ethyl acetate(3×50 mL). The combined organic layers were washed with brine, driedover anhydrous sodium sulfate, filtered and concentrated under reducedpressure to afford the title compound (450 mg crude, 87.7%) as a yellowoil. LC-MS (Method S): m/z=304.1 [M+H]⁺, 0.610 min.

Step 5: Preparation of7-azido-5-methyl-8,9-dihydro-5H-pyrazino[2,3-b]azepin-6(7H)-one

Sodium azide (290 mg, 4.47 mmol) was added to a stirring mixture of7-iodo-5-methyl-8,9-dihydro-5H-pyrazino[2,3-b]azepin-6(7H)-one (450 mg,1.49 mmol) in N,N-dimethylformamide (50 mL). After stirred at roomtemperature for 3 hours, the reaction mixture was quenched by theaddition of water (40 mL) and extracted with ethyl acetate (3×50 mL).The combined organic layers were washed with brine, dried over sodiumsulfate, filtered and concentrated under vacuum to afford the titlecompound (260 mg crude) as a yellow oil. LC-MS (Method S): m/z=219.1[M+H]⁺, 0.600 min.

Step 6: Preparation of7-amino-5-methyl-8,9-dihydro-5H-pyrazino[2,3-b]azepin-6(7H)-one

7-Azido-5-methyl-8,9-dihydro-5H-pyrazino[2,3-b]azepin-6(7H)-one (260 mg,1.2 mmol) in methanol (20 mL) was hydrogenated in the presence ofpalladium on carbon (10%, 26 mg) under a hydrogen atmosphere (2-3 atm).After stirring for 5 hours at room temperature under a hydrogenatmosphere, the reaction mixture was filtered through Celite. Thefiltrate was concentrated under reduced pressure and dried under highvacuum to afford the title compound (200 mg, 88%) as a colorless oil.LC-MS (Method S): m/z=193.1 [M+H]⁺, 0.356 min.

Step 7. Preparation of4-fluoro-1-(2-fluorobenzyl)-N-(5-methyl-6-oxo-6,7,8,9-tetrahydro-1H-pyrazino[2,3-b]azepin-7-yl)-1H-pyrazole-3-carboxamide

The crude product obtained using Amide Coupling Procedure C was purifiedby Prep-HPLC with the following conditions: Column: XBridge Shield C18OBD Column, 5 μm, 19×150 mm; Mobile Phase A: Water (10 mmol/L NH₄HCO₃),Mobile Phase B: MeCN; Flow rate: 20 mL/min; Gradient: 35% B to 50% B in8 min; UV 254 & 220 nm; Rt: 6.82 min to afford the title compound (30mg, 28%) as a white solid. LC-MS (Method O): m/z=413.1 [M+H]⁺, 1.396min.

Step 8: Preparation of(S)-4-fluoro-1-(2-fluorobenzyl)-N-(5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrazino[2,3-b]azepin-7-yl)-1H-pyrazole-3-carboxamideand(R)-4-fluoro-1-(2-fluorobenzyl)-N-(5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrazino[2,3-b]azepin-7-yl)-1H-pyrazole-3-carboxamide

The racemate of4-fluoro-1-(2-fluorobenzyl)-N-(5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrazino[2,3-b]azepin-7-yl)-1H-pyrazole-3-carboxamide(30.0 mg, 0.07 mmol) was separated by Prep-Chiral-HPLC with thefollowing conditions: Column: CHIRALPAK IF, 2×25 cm, 5 μm; Mobile PhaseA: Hexane, Mobile Phase B: EtOH; Flow rate: 16 mL/min; Gradient: 50% Bto 50% B in 30 min; UV 254 & 220 nm; Rt1: 17.00 min; Rt2: 24.16 min toafford the title compounds:

Example 178A (first eluting isomer): ¹H NMR (400 MHz, CD₃OD-d₄) δ 8.48(d, J=2.8 Hz, 1H), 8.39 (d, J=2.8 Hz, 1H), 7.77 (d, J=4.4 Hz, 1H),7.45-7.38 (m, 1H), 7.34-7.29 (m, 1H), 7.24-7.15 (m, 2H), 5.41 (s, 2H),4.58-4.52 (m, 1H), 3.50 (s, 3H), 3.18-3.08 (m, 1H), 3.04-2.98 (m, 1H),2.80-2.69 (m, 1H), 2.41-2.31 (m, 1H). LC-MS (Method T): m/z=413.1[M+H]⁺, 1.198 min.

Example 178B (second eluting isomer): ¹H NMR (400 MHz, CD₃OD-d₄) δ 8.47(d, J=2.8 Hz, 1H), 8.38 (d, J=2.8 Hz, 1H), 7.78 (d, J=4.4 Hz, 1H),7.45-7.38 (m, 1H), 7.34-7.29 (m, 1H), 7.25-7.15 (m, 2H), 5.41 (s, 2H),4.58-4.52 (m, 1H), 3.50 (s, 3H), 3.19-3.08 (m, 1H), 3.05-2.98 (m, 1H),2.81-2.69 (m, 1H), 2.41-2.32 (m, 1H). LC-MS (Method X): m/z=413.1[M+H]⁺, 2.354 min.

Example 179A and 179B:4-fluoro-1-(2-fluorobenzyl)-N-((7S,7aS,8aR)-5-methyl-6-oxo-5,6,7,7a,8,8a-hexahydrocyclopropa[d]pyrazino[2,3-b]azepin-7-yl)-1H-pyrazole-3-carboxamideand4-fluoro-1-(2-fluorobenzyl)-N-((7R,7aR,8aS)-5-methyl-6-oxo-5,6,7,7a,8,8a-hexahydrocyclopropa[d]pyrazino[2,3-b]azepin-7-yl)-1H-pyrazole-3-carboxamide

The crude product obtained using Amide Coupling Procedure C was purifiedby Prep-TLC (ethyl acetate/petroleum ether, 3/1) to afford the titlecompound as a white solid.

The racemate was separated by Prep-Chiral-HPLC with the followingconditions: Column: CHIRALPAK IF, 2×25 cm, 5 μm; Mobile Phase A: Hexane,Mobile Phase B: EtOH; Flow rate: 16 mL/min; Gradient: 50% B to 50% B in38 min; UV 254 & 220 nm; Rt1: 22.995; Rt2: 30.882 to afford the titlecompounds:

Example 179A (first eluting isomer): ¹H NMR (400 MHz, CD₃OD-d₄) δ 8.30(dd, J=2.4, 6.4 Hz, 2H), 7.68 (d, J=4.4 Hz, 1H), 7.34-7.27 (m, 1H),7.25-7.20 (m, 1H), 7.13-7.04 (m, 2H), 5.23 (s, 2H), 4.66 (s, 1H), 3.31(s, 3H), 2.54-2.47 (m, 1H), 2.17-2.10 (m, 1H), 1.43-1.37 (m, 1H),1.22-1.15 (m, 1H). LC-MS (Method D): m/z=425.0 [M+H]⁺, 1.679 min.

Example 179B (second eluting isomer): ¹H NMR (400 MHz, CD₃OD-d₄) δ 8.42(dd, J=3.2, 6.8 Hz, 2H), 7.80 (d, J=4.4 Hz, 1H), 7.45-7.39 (m, 1H),7.37-7.32 (m, 1H), 7.25-7.16 (m, 2H), 5.44 (s, 2H), 4.78 (s, 1H), 3.42(s, 3H), 2.65-2.58 (m, 1H), 2.28-2.22 (m, 1H), 1.54-1.49 (m, 1H),1.33-1.27 (m, 1H). LC-MS (Method D): m/z=425.0 [M+H]⁺, 1.684 min.

Example 180A and 180B:(S)—N-(5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrazino[2,3-b]azepin-7-yl)-5-(1-phenylcyclopropyl)-1,3,4-oxadiazole-2-carboxamideand(R)—N-(5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrazino[2,3-b]azepin-7-yl)-5-(1-phenylcyclopropyl)-1,3,4-oxadiazole-2-carboxamide

The crude product obtained using Amide Coupling Procedure C was purifiedby Prep-TLC (ethyl acetate/petroleum ether, 1/1) to afford the titlecompound.

The racemate ofN-(5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrazino[2,3-b]azepin-7-yl)-5-(1-phenylcyclopropyl)-1,3,4-oxadiazole-2-carboxamide(30 mg, 0.08 mmol) was separated by Prep-Chiral-HPLC with the followingconditions: Column: CHIRALPAK IE, 2×25 cm, 5 μm; Mobile Phase A: Hexane,Mobile Phase B: MeOH; Flow rate: 20 mL/min; Gradient: 100% B to 100% Bover 16 min; UV 254 & 220 nm; Rt 1: 10.459 min; Rt 2: 12.463 min toafford the title compounds:

Example 180A (first eluting isomer): ¹H NMR (400 MHz, CD₃OD-d₄) δ 8.49(d, J=2.4 Hz, 1H), 8.40 (d, J=2.8 Hz, 1H), 7.48-7.46 (m, 2H), 7.41-7.31(m, 3H), 4.57-4.51 (m, 1H), 3.49 (s, 3H), 3.18-3.09 (m, 1H), 3.05-2.99(m, 1H), 2.74-2.63 (m, 1H), 2.50-2.41 (m, 1H), 1.80-1.77 (m, 2H),1.59-1.55 (m, 2H). LC-MS (Method D): m/z=405.0 [M+H]⁺, 1.260 min.

Example 180B (second eluting isomer): ¹H NMR (400 MHz, CD₃OD-d₄) δ 8.49(d, J=2.4 Hz, 1H), 8.40 (d, J=2.8 Hz, 1H), 7.49-7.46 (m, 2H), 7.42-7.31(m, 3H), 4.57-4.50 (m, 1H), 3.50 (s, 3H), 3.18-3.09 (m, 1H), 3.06-2.99(m, 1H), 2.74-2.63 (m, 1H), 2.50-2.40 (m, 1H), 1.81-1.77 (m, 2H),1.60-1.55 (m, 2H). LC-MS (Method D): m/z=405.0 [M+H]⁺, 1.261 min.

Example 181A and 181B:5-(3-cyanobenzyl)-N-((1aR,2R,8bS)-5,7-difluoro-3-oxo-1,1a,2,3,4,8b-hexahydrobenzo[b]cyclopropa[d]azepin-2-yl)-4H-1,2,4-triazole-3-carboxamideand5-(3-cyanobenzyl)-N-((1aS,2S,8bR)-5,7-difluoro-3-oxo-1,1a,2,3,4,8b-hexahydrobenzo[b]cyclopropa[d]azepin-2-yl)-4H-1,2,4-triazole-3-carboxamide

The crude product obtained using Amide Coupling Procedure C was purifiedby Prep-HPLC with the following conditions: Column: XBridge Shield C18OBD Column, 5 μm, 19×150 mm; Mobile Phase A: Water (10 mmol/L NH₄HCO₃),Mobile Phase B: MeCN; Flow rate: 20 mL/min; Gradient: 30% B to 53% Bover 8 min; 254 & 220 nm Rt: 7.43 min to afford the title compound as awhite solid.

The racemate was separated by Prep-Chiral-HPLC with the followingconditions: Column: CHIRALPAK IE, 2×25 cm, 5 μm; Mobile Phase A:Hexane:DCM=5:1, Mobile Phase B: EtOH; Flow rate: 16 mL/min; Gradient:50% B to 50% B over 23 min; 254 & 220 nm; Rt1: 9.885; Rt2: 16.633 toafford the title compounds:

Example 181A (first eluting isomer): ¹H NMR (400 MHz, CD₃OD-d₄) δ 7.71(s, 1H), 7.65-7.61 (m, 2H), 7.54-7.48 (m, 1H), 7.18-7.05 (m, 1H),6.99-6.90 (m, 1H), 4.81 (s, 1H), 4.24 (s, 2H), 2.31-2.22 (m, 1H),2.15-2.07 (m, 1H), 1.74-1.63 (m, 1H), 1.24-1.14 (m, 1H). LC-MS (MethodJ): m/z=435.4 [M+H]⁺, 1.200 min.

Example 181B (second eluting isomer): ¹H NMR (400 MHz, CD₃OD-d₄) δ 7.70(s, 1H), 7.66-7.62 (m, 2H), 7.55-7.49 (m, 1H), 7.19-7.07 (m, 1H),6.98-6.91 (m, 1H), 4.81 (s, 1H), 4.24 (s, 2H), 2.32-2.23 (m, 1H),2.16-2.07 (m, 1H), 1.67-1.59 (m, 1H), 1.23-1.14 (m, 1H). LC-MS (MethodV): m/z=435.1 [M+H]⁺, 3.354 min.

Example 182A and 182B:(R)-4-fluoro-N-(5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrazino[2,3-b]azepin-7-yl)-1-((2-methylpyridin-3-yl)methyl)-1H-pyrazole-3-carboxamideand(S)-4-fluoro-N-(5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrazino[2,3-b]azepin-7-yl)-1-((2-methylpyridin-3-yl)methyl)-1H-pyrazole-3-carboxamide

Step 1: Preparation of ethyl4-fluoro-1-((2-methylpyridin-3-yl)methyl)-1H-pyrazole-3-carboxylate

3-(Bromomethyl)-2-methylpyridine (283 mg, 1.52 mmol) was added to astirring mixture of ethyl 4-fluoro-1H-pyrazole-3-carboxylate (200 mg,1.27 mmol) and cesium carbonate (1.24 g, 3.80 mmol) inN,N-dimethylformamide (20 mL). The reaction mixture was stirred at roomtemperature for 3 hours, quenched by the addition of water (100 mL) andextracted with ethyl acetate (3×100 mL). The combined organic layerswere washed with brine, dried over anhydrous sodium sulfate, filteredand concentrated under vacuum. The residue was purified by columnchromatography (ethyl acetate/petroleum ether, 1/4) to afford the titlecompound (300 mg, 90.9%) as a white solid. LC-MS (Method C): m/z=264.1[M+H]⁺, 1.291 min.

Step 2: Preparation of4-fluoro-1-((2-methylpyridin-3-yl)methyl)-1H-pyrazole-3-carboxylic acid

Lithium hydroxide (82 mg, 3.42 mmol) was added to a mixture of ethyl4-fluoro-1-((2-methyl pyridin-3-yl)methyl)-1H-pyrazole-3-carboxylate(300 mg, 1.14 mmol) in tetrahydrofuran (12 mL) and water (4 mL). Thereaction mixture was stirred at room temperature overnight. Afterremoval of tetrahydrofuran under reduced pressure, the resultingsolution was adjusted to pH=6 with aqueous hydrochloric acid (1 N, 10mL), and extracted with ethyl acetate (3×60 mL). The combined organiclayers were washed with brine, dried over anhydrous sodium sulfate,filtered and concentrated under vacuum to afford the title compound (220mg crude) as a white solid. LC-MS (Method C): m/z=236.0 [M+H]⁺, 0.365min.

Step 3: Preparation of4-fluoro-N-(5-methyl-6-oxo-6,7,8,9-tetrahydro-1H-pyrazino[2,3-b]azepin-7-yl)-1-((2-methylpyridin-3-yl)methyl)-1H-pyrazole-3-carboxamide

The crude product obtained using Amide Coupling Procedure C was purifiedby Prep-HPLC with the following conditions: Column: XBridge Shield C18OBD Column, 5 μm, 19×150 mm; Mobile Phase A: Water (10 mmol/L NH₄HCO₃),Mobile Phase B: MeCN; Flow rate: 20 mL/min; Gradient: 20% B to 33% Bover 8 min; UV 254 & 220 nm; Rt: 7.28 min to afford the title compound.LC-MS (Method Y): m/z=410.2 [M+H]⁺, 0.841 min.

Step 4: Preparation of(R)-4-fluoro-N-(5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrazino[2,3-b]azepin-7-yl)-1-((2-methylpyridin-3-yl)methyl)-1H-pyrazole-3-carboxamideand(S)-4-fluoro-N-(5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrazino[2,3-b]azepin-7-yl)-1-((2-methylpyridin-3-yl)methyl)-1H-pyrazole-3-carboxamide

The racemate of4-fluoro-N-(5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrazino[2,3-b]azepin-7-yl)-1-((2-methylpyridin-3-yl)methyl)-1H-pyrazole-3-carboxamide(40 mg, 0.10 mmol) was separated by Prep-Chiral-HPLC with the followingconditions: Column: CHIRAL ART Cellulose-SB, 2×25 cm, 5 μm; Mobile PhaseA: Hexane, Mobile Phase B: EtOH; Flow rate: 20 mL/min; Gradient: 50B %to 50B % over 13 min; UV 254 & 220 nm; Rt 1: 9.428 min; Rt 2: 11.106 minto afford the title compounds:

Example 182A (first eluting isomer): ¹H NMR (400 MHz, CD₃OD-d₄) δ 8.49(d, J=2.8 Hz, 1H), 8.42-8.39 (m, 2H), 7.80 (d, J=4.4 Hz, 1H), 7.51-7.48(m, 1H), 7.33-7.29 (m, 1H), 5.45 (s, 2H), 4.58-4.53 (m, 1H), 3.50 (s,3H), 3.18-3.08 (m, 1H), 3.04-2.98 (m, 1H), 2.81-2.70 (m, 1H), 2.58 (s,3H), 2.42-2.31 (m, 1H). LC-MS (Method D): m/z=410.0 [M+H]⁺, 0.715 min.

Example 182B (second eluting isomer): ¹H NMR (400 MHz, CD₃OD-d₄) δ 8.49(d, J=2.8 Hz, 1H), 8.42-8.39 (m, 2H), 7.80 (d, J=4.4 Hz, 1H), 7.52-7.48(m, 1H), 7.34-7.29 (m, 1H), 5.45 (s, 2H), 4.58-4.53 (m, 1H), 3.50 (s,3H), 3.18-3.07 (m, 1H), 3.05-2.98 (m, 1H), 2.81-2.70 (m, 1H), 2.58 (s,3H), 2.42-2.30 (m, 1H). LC-MS (Method D): m/z=410.0 [M+H]⁺, 0.720 min.

Example 183A and 183B:1-benzyl-4-fluoro-N-((1aR,2R,8bS)-4-trideuteriomethyl-7-(methylsulfonyl)-3-oxo-1,1a,2,3,4,8b-hexahydrobenzo[b]cyclopropa[d]azepin-2-yl)-1H-pyrazole-3-carboxamideand1-benzyl-4-fluoro-N-((1aS,2S,8bR)-4-trideuteriomethyl-7-(methylsulfonyl)-3-oxo-1,1a,2,3,4,8b-hexahydrobenzo[b]cyclopropa[d]azepin-2-yl)-1H-pyrazole-3-carboxamide

Step 1: Preparation of 7-bromo-4,5-dihydro-1H-benzo[b]azepin-2(3H)-one

A solution of bromine (8 mL, 155 mmol) in acetic acid (100 mL) was addedto a solution of 4,5-Dihydro-1H-benzo[b]azepin-2(3H)-one (10 g, 62 mmol)and sulfuric acid (5 mL) in acetic acid (100 mL) dropwise at 0° C. Afterstirring overnight at room temperature, the reaction mixture was pouredinto ice water (200 mL), neutralized with ammonium hydroxide (28%, 100mL) and extracted with ethyl acetate (3×80 mL). The combined organiclayers were washed with brine, dried over sodium sulfate, filtered andconcentrated under vacuum. The residue was purified by columnchromatography (ethyl acetate/petroleum ether, 99/1) to afford the titlecompound (11.5 g, 77%) as a colorless oil. LC-MS (Method C): m/z=240.0[M+H]⁺, 1.152 min.

Step 2: Preparation of 7-bromo-1-trideuteriomethyl-4,5-dihydro-1H-benzo[b]azepin-2(3H)-one

Trideuterated iodomethane (5.9 g, 41 mmol) was added dropwise to astirring mixture of 7-bromo-4,5-dihydro-1H-benzo[b]azepin-2(3H)-one (9g, 38 mmol) and cesium carbonate (13.4 g, 41 mmol) inN,N-dimethylformamide (30 mL). The reaction mixture was stirred for 2hours at room temperature, diluted with water (60 mL) and extracted withethyl acetate (3×50 mL). The combined organic layers were washed withbrine, dried over anhydrous sodium sulfate, filtered and concentratedunder vacuum. The residue was purified by column chromatography(methanol/dichloromethane, 1/20) to afford the title compound (7.2 g,75%) as a yellow solid. LC-MS (Method C): m/z=257.1 [M+H]⁺, 1.234 min.

Step 3: Preparation of1-trideuteriomethyl-7-(methylsulfonyl)-4,5-dihydro-1H-benzo[b]azepin-2(3H)-one

Cuprous iodide (304 mg, 1.6 mmol) was added to a mixture of7-bromo-1-trideuteriomethyl-4,5-dihydro-1H-benzo[b]azepin-2(3H)-one (4.1g, 16 mmol), L-proline (368 mg, 3.2 mmol), sodium hydroxide (64 mg, 1.6mmol) and sodium methanesulphinate (8.16 g, 80 mmol) in dimethylsulfoxide (20 mL) under nitrogen atmosphere. The reaction mixture wasstirred overnight at 120° C. After cooling to room temperature, thereaction mixture was diluted with saturated aqueous ammonium chloride(40 mL) and extracted with ethyl acetate (3×50 mL). The combined organiclayers were dried over anhydrous sodium sulfate, filtered andconcentrated under vacuum. The residue was purified by columnchromatography (methanol/dichloromethane, 1/20) to afford the titlecompound (2.7 g, 66%) as a yellow solid. LC-MS (Method C): m/z=257.1[M+H]⁺, 0.907 min.

Step 4: Preparation of3-iodo-1-trideuteriomethyl-7-(methylsulfonyl)-4,5-dihydro-1H-benzo[b]azepin-2(3H)-one

N¹,N¹,N²,N²-tetramethylethane-1,2-diamine (3.8 g, 33 mmol) was added toa stirring mixture of1-trideuteriomethyl-7-(methylsulfonyl)-4,5-dihydro-1H-benzo[b]azepin-2(3H)-one(2.7 g, 11 mmol) in dichloromethane (40 mL) at 0° C., followed by theaddition of iodotrimethylsilane (6.6 g, 33 mmol) dropwise over 30minutes. After stirring for 1 hour at 0° C., a solution of iodine (4.2g, 16.5 mmol) in dichloromethane (100 mL) was added. The reactionmixture was stirred for 2 hours at 0° C., quenched by the addition ofaqueous sodium thiosulfate (5%, 60 mL) and extracted with ethyl acetate(3×50 mL). The combined organic layers were washed with brine, driedover anhydrous sodium sulfate, filtered and concentrated under vacuum.The residue was purified by column chromatography (dichloromethane) toafford the title compound (3.5 g, 88%) as a yellow solid. LC-MS (MethodS): m/z=382.9 [M+H]⁺, 0.826 min.

Step 5: Preparation of 1-trideuteratedmethyl-7-(methylsulfonyl)-1H-benzo[b]azepin-2(3H)-one

1,8-Diazabicyclo[5.4.0]undec-7-ene (3.8 g, 25.2 mmol) was added to astirring mixture of 3-iodo-1-trideuteratedmethyl-7-(methylsulfonyl)-4,5-dihydro-1H-benzo[b]azepin-2(3H)-one (3.2g, 8.4 mmol) in N,N-dimethylformamide (10 mL) at room temperature. Thereaction mixture was stirred overnight at 80° C., quenched by theaddition of water (30 mL) and extracted with ethyl acetate (3×50 mL).The combined organic layers were washed with brine, dried over anhydroussodium sulfate, filtered and concentrated under vacuum. The residue waspurified by column chromatography (dichloromethane) to afford the titlecompound (1.8 g, 85%) as a yellow solid. LC-MS (Method T): m/z=255.2[M+H]⁺, 0.698 min.

Step 6: Preparation of4-trideuteriomethyl-7-(methylsulfonyl)-1,1a,2,8b-tetrahydrobenzo[b]cyclopropa[d]azepin-3(4H)-one

1-Methyl-1-nitrosourea (7.4 g, 70 mmol) was added to a solution ofpotassium hydroxide (14 g, 350 mmol) in water (21 mL) and ether (100 mL)at 0° C. The resulting mixture was stirred for 1 hour at 0° C. and thenthe organic phase was separated to provide a solution of diazomethane inether (100 mL). The solution of diazomethane (100 ml) was added to themixture of1-trideuteriomethyl-7-(methylsulfonyl)-1H-benzo[b]azepin-2(3H)-one (1.8g, 7 mmol) in tetrahydrofuran (30 mL) dropwise, followed by addition ofa mixture of palladium diacetate (158 mg, 0.7 mmol) in tetrahydrofuran(10 mL) dropwise at 0° C. The reaction mixture was stirred overnight atroom temperature. The solids were removed by filtration and the filtratewas concentrated under vacuum to afford the title compound (1.5 g crude)as a yellow oil. LC-MS (Method E): m/z=268.9 [M+H]⁺, 0.757 min.

Step 7. Preparation oftrans-2-iodo-4-trideuteriomethyl-7-(methylsulfonyl)-1,1a,2,8b-tetrahydrobenzo[b]cyclopropa[d]azepin-3(4H)-one

N¹,N¹,N²,N²-tetramethylethane-1,2-diamine (1.95 g, 16.8 mmol) was addedto a stirring mixture of4-trideuteriomethyl-7-(methylsulfonyl)-1,1a,2,8b-tetrahydrobenzo[b]cyclopropa[d]azepin-3(4H)-one (1.5 g, 5.6 mmol) in dichloromethane (30 mL) at 0°C., followed by the addition of iodotrimethylsilane (3.4 g, 16.8 mmol)dropwise over 30 minutes. After stirring for 1 hour at 0° C., a solutionof iodine (2.1 g, 8.4 mmol) in dichloromethane (50 mL) was added. Thereaction mixture was stirred for 2 hours at 0° C., quenched by theaddition of aqueous sodium thiosulfate (5%, 40 mL) and extracted withethyl acetate (3×50 mL). The combined organic layers were washed withbrine, dried over anhydrous sodium sulfate, filtered and concentratedunder vacuum to afford the title compound (1.6 g crude) as a yellow oil.LC-MS (Method S): m/z=394.9 [M+H]⁺, 0.892 min.

Step 8: Preparation ofcis-2-azido-4-trideuteriomethyl-7-(methylsulfonyl)-1,1a,2,8b-tetrahydrobenzo[b]cyclopropa[d]azepin-3(4H)-one

Sodium azide (390 mg, 6 mmol) was added to a stirring mixture oftrans-2-iodo-4-trideuteriomethyl-7-(methylsulfonyl)-1,1a,2,8b-tetrahydrobenzo[b]cyclopropa[d]azepin-3(4H)-one(1.6 g, 4 mmol) in N,N-dimethylformamide (10 mL). The reaction mixturewas stirred overnight at room temperature, quenched with water (40 mL)and extracted with ethyl acetate (3×50 mL). The combined organic layerswere washed with brine, dried over anhydrous sodium sulfate, andfiltered. The filtrate was concentrated under vacuum to afford the titlecompound (800 mg crude) as a yellow oil. LC-MS (Method S): m/z=309.9[M+H]⁺, 0.855 min.

Step 9: Preparation ofcis-2-amino-4-trideuteriomethyl-7-(methylsulfonyl)-1,1a,2,8b-tetrahydrobenzo[b]cyclopropa[d]azepin-3(4H)-one

A solution ofcis-2-azido-4-trideuteriomethyl-7-(methylsulfonyl)-1,1a,2,8b-tetrahydrobenzo[b]cyclopropa[d]azepin-3(4H)-one(800 mg, 2.59 mmol) in methanol (30 mL) was hydrogenated in the presenceof palladium on carbon (10%, 100 mg) under hydrogen atmosphere (2-3atm). After stirring for 2 hours at room temperature under hydrogenatmosphere, the reaction mixture was filtered through Celite. Thefiltrate was concentrated under vacuum and the resulting residue waspurified by column chromatography (dichloromethane) to afford the titlecompound (500 mg, 68%) as a yellow solid. LC-MS (Method F): m/z=283.9[M+H]⁺, 0.715 min.

Step 10: Preparation of1-benzyl-4-fluoro-N-(cis-4-trideuteriomethyl-7-(methylsulfonyl)-3-oxo-1,1a,2,3,4,8b-hexahydrobenzo[b]cyclopropa[d]azepin-2-yl)-1H-pyrazole-3-carboxamide

The crude product obtained using Amide Coupling Procedure C was purifiedby Prep-HPLC with the following conditions: Column: Xbridge Prep C18, 5μm, 19×150 mm; Mobile Phase A: Water (0.1% NH₄HCO₃), Mobile Phase B:MeCNFlow rate: 20 mL/min; Gradient: 32% B to 55% B over 8 min; 254 & 220nm; Rt: 7.38 min to afford the title compound. LC-MS (Method E):m/z=486.1 [M+H]⁺, 1.037 min.

Step 11: Preparation of1-benzyl-4-fluoro-N-((1aR,2R,8bS)-4-trideuteriomethyl-7-(methylsulfonyl)-3-oxo-1,1a,2,3,4,8b-hexahydrobenzo[b]cyclopropa[d]azepin-2-yl)-1H-pyrazole-3-carboxamideand1-benzyl-4-fluoro-N-((1aS,2S,8bR)-4-trideuteriomethyl-7-(methylsulfonyl)-3-oxo-1,1a,2,3,4,8b-hexahydrobenzo[b]cyclopropa[d]azepin-2-yl)-1H-pyrazole-3-carboxamide

The racemate of1-benzyl-4-fluoro-N-(cis-4-trideuteriomethyl-7-(methylsulfonyl)-3-oxo-1,1a,2,3,4,8b-hexahydrobenzo[b]cyclopropa[d]azepin-2-yl)-1H-pyrazole-3-carboxamidewas separated by Prep-Chiral-HPLC with the following conditions: Column:CHIRALPAK IA, 2.12×15 cm, 5 μm; Mobile Phase A: Hexane, Mobile Phase B:EtOH; Flow rate: 20 mL/min; Gradient: 50% B to 50% B over 22 min; 254 &220 nm; Rt1: 10.61; Rt2: 16.166 to afford the title compounds:

Example 183A (first eluting isomer): ¹H NMR (400 MHz, CD₃OD-d₄) δ 8.05(d, J=2.3 Hz, 1H), 7.86 (dd, J=8.5, 2.3 Hz, 1H), 7.75 (d, J=4.5 Hz, 1H),7.53 (d, J=8.5 Hz, 1H), 7.42-7.31 (m, 5H), 5.33 (s, 2H), 4.66 (s, 1H),3.17 (s, 3H), 2.47-2.37 (m, 1H), 2.15-2.06 (m, 1H), 1.38-1.30 (m, 1H),1.26-1.17 (m, 1H). LC-MS (Method V): m/z=486.1 [M+H]⁺, 3.132 min.

Example 183B (second eluting isomer): ¹H NMR (400 MHz, CD₃OD-d₄) δ 8.05(d, J=2.3 Hz, 1H), 7.86 (dd, J=8.5, 2.3 Hz, 1H), 7.76 (d, J=4.5 Hz, 1H),7.53 (d, J=8.5 Hz, 1H), 7.43-7.30 (m, 5H), 5.33 (s, 2H), 4.66 (s, 1H),3.17 (s, 3H), 2.47-2.37 (m, 1H), 2.15-2.07 (m, 1H), 1.37-1.31 (m, 1H),1.28-1.17 (m, 1H). LC-MS (Method D): m/z=486.1 [M+H]⁺, 1.390 min.

Example 184:(S)-4-fluoro-1-((1-methyl-1H-pyrazol-4-yl)methyl)-N-(5-methyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepin-3-yl)-1H-pyrazole-3-carboxamide

Cesium carbonate (453 mg, 1.39 mmol) was added to a stirring mixture of(S)-4-fluoro-N-(5-methyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepin-3-yl)-1H-pyrazole-3-carboxamide(100 mg, 0.33 mmol) and 4-(bromomethyl)-1-methyl-1H-pyrazolehydrochloride (208 mg, 0.82 mmol) in N,N-dimethylformamide (7 mL). Afterstirring for 3 hours at room temperature, the reaction mixture wasquenched by the addition of water (50 mL) and extracted withdichloromethane (3×50 mL). The combined organic layers were dried overanhydrous sodium sulfate, filtered and concentrated under vacuum. Theresidue was purified by Prep-HPLC with the following conditions: Column;Xbridge Prep C18, 5 μm, 19×150 mm; Mobile Phase A; Water (0.1 mmol/LNH₄HCO₃), Mobile Phase B; MeCN; Flow rate: 20 mL/min; Gradient: 15% B to36% B over 10 min; UV 254 & 220 nm to afford the title compound: ¹H NMR(300 MHz, DMSO-d₆) δ 8.37 (dd, J=4.8, 1.5 Hz, 1H), 8.22 (d, J=7.5 Hz,1H), 8.01 (d, J=4.2 Hz, 1H), 7.75 (s, 1H), 7.71 (dd, J=8.1, 1.5 Hz, 1H),7.49 (s, 1H), 7.34 (dd, J=8.1, 4.8 Hz, 1H), 5.19 (s, 2H), 4.91-4.81 (m,1H), 4.69 (dd, J=11.1, 9.6 Hz, 1H), 4.53 (dd, J=9.6, 7.5 Hz, 1H), 3.82(s, 3H), 3.37 (s, 3H). LC-MS (Method D): m/z=400.0 [M+H]⁺, 1.357 min.

Example 188:(S)-5-benzyl-N-(5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrazino[2,3-b]azepin-7-yl)isoxazole-3-carboxamide

The crude product was purified by Prep-TLC (ethyl acetate/hexane, 3/1)to afford the racemate. LC-MS (Method E): m/z=378.2 [M+H]⁺, 0.998 min.The racemate of5-benzyl-N-(5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrazino[2,3-b]azepin-7-yl)isoxazole-3-carboxamidewas separated by Prep-Chiral-HPLC with the following conditions: Column:CHIRALPAK IA, 2×25 cm, 5 μm; Mobile Phase A: Hexane:DCM=5:1, MobilePhase B: EtOH; Flow rate: 15 mL/min; Gradient: 50% B to 50% B in 20 min;UV 254 & 220 nm; Rt1: 11.1; Rt2: 15.01 to afford the title compound asthe first eluting isomer: ¹H NMR (400 MHz, CD₃OD-d₄) δ 8.48-8.35 (m,2H), 7.35-7.23 (m, 5H), 6.38 (s, 1H), 4.48 (dd, J=8.0, 12.0 Hz, 1H),4.16 (s, 2H), 3.47 (s, 3H), 3.15-3.05 (m, 1H), 3.02-2.95 (m, 1H),2.72-2.61 (m, 1H), 2.43-2.34 (m, 1H). LC-MS (Method D): m/z=378.0[M+H]⁺, 1.645 min.

Example 190:(S)-5-benzyl-N-(5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrazino[2,3-b]azepin-7-yl)-1,3,4-oxadiazole-2-carboxamide

The residue was purified by Prep-TLC (ethyl acetate/hexane, 3/1) toafford the racemate. LC-MS (Method C): m/z=378.1 [M+H]⁺, 1.141 min. Theracemate of5-benzyl-N-(5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrazino[2,3-b]azepin-7-yl)-1,3,4-oxadiazole-2-carboxamidewas separated by Prep-Chiral-HPLC with the following conditions: Column:CHIRALPAK IA, 2×25 cm, 5 μm; Mobile Phase A: Hexane:DCM=5:1, MobilePhase B: EtOH; Flow rate: 15 mL/min; Gradient: 50% B to 50% B in 20 min;UV 254 & 220 nm; Rt1: 11.1; Rt2: 15.01 to afford the title compound asthe first eluting isomer: ¹H NMR (400 MHz, CD₃OD-d₄) δ 8.46 (d, J=2.8Hz, 1H), 8.37 (d, J=2.4 Hz, 1H), 7.37-7.26 (m, 5H), 4.53 (dd, J=12.0,7.6 Hz, 1H), 4.32 (s, 2H), 3.48 (s, 3H), 3.18-3.06 (m, 1H), 3.03-2.97(m, 1H), 2.73-2.62 (m, 1H), 2.49-2.39 (m, 1H). LC-MS (Method J):m/z=379.1 [M+H]⁺, 1.072 min.

Example192:5-benzyl-N-((2R,3S)-2,5-dimethyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepin-3-yl)oxazole-2-carboxamide

The crude product obtained was purified by Prep-HPLC with the followingconditions: Column: Xbridge Prep C18, 5 μm, 19×150 mm; Mobile Phase A:Water (0.1% NH₄HCO₃), Mobile Phase B: MeCN; Flow rate: 20 mL/min;Gradient: 35% B to 66% B over 8 min; UV 254 & 220 nm; Rt: 6.98 min toafford the title compound. ¹H NMR (400 MHz, CD₃OD-d₄) δ 8.34 (dd, J=4.8,1.6 Hz, 1H), 7.69 (dd, J=8.0, 1.6 Hz, 1H), 7.38-7.22 (m, 6H), 7.04 (s,1H), 5.07-4.96 (m, 2H), 4.13 (s, 2H), 3.50 (s, 3H), 1.42 (d, J=5.9 Hz,3H). LC-MS (Method D): m/z=393.1 [M+H]⁺, 1.524 min.

Example 193:5-benzyl-N-((3S,4R)-1,4-dimethyl-2-oxo-1,2,3,4-tetrahydropyrido[2,3-b][1,4]oxazepin-3-yl)-1,3,4-oxadiazole-2-carboxamide

The crude product was purified by Prep-TLC (ethyl acetate/petroleumether, 3/1) to afford the title compound: ¹H NMR (400 MHz, CD₃OD-d₄) δ8.22-8.19 (m, 1H), 7.94-7.90 (m, 1H), 7.43-7.39 (m, 1H), 7.35-7.26 (m,5H), 5.14-5.07 (m, 2H), 4.31 (s, 2H), 3.44 (s, 3H), 1.45 (d, J=6.0 Hz,3H). LC-MS (Method T): m/z=394.1 [M+H]⁺, 1.202 min.

Example 194:5-benzyl-N-((7S,7aS,8aR)-5-methyl-6-oxo-5,6,7,7a,8,8a-hexahydrocyclopropa[d]pyrazino[2,3-b]azepin-7-yl)oxazole-2-carboxamide

The crude product was purified by Prep-TLC (ethyl acetate/petroleumether, 3/1) to afford the racemate. LC-MS (Method E): m/z=390.2 [M+H]⁺,1.018 min. The racemate of5-benzyl-N-cis-5-methyl-6-oxo-5,6,7,7a,8,8a-hexahydrocyclopropa[d]pyrazino[2,3-b]azepin-7-yl)-oxazole-2-carboxamide(50 mg, 0.13 mmol) was separated by Prep-Chiral-HPLC with the followingconditions: Column: CHIRAL ART Cellulose-SB, 2×25 cm, 5 μm; Mobile PhaseA: MTBE, Mobile Phase B: EtOH; Flow rate: 20 mL/min; Gradient: 30 B to30 B in 15 min; UV 254 & 220 nm; Rt1: 7.635; Rt2: 9.685 to afford thetitle compound as the first eluting isomer: ¹H NMR (400 MHz, CD₃OD-d₄) δ8.45-8.40 (m, 2H), 7.39-7.23 (m, 5H), 7.04 (s, 1H), 4.77 (s, 1H), 4.14(s, 2H), 3.42 (s, 3H), 2.67-2.59 (m, 1H), 2.28-2.20 (m, 1H), 1.57-1.50(m, 1H), 1.37-1.28 (m, 1H). LC-MS (Method D): m/z=390.1 [M+H]⁺, 1.361min.

Example195:1-benzyl-N-((7S,7aS,8aR)-5-methyl-6-oxo-5,6,7,7a,8,8a-hexahydrocyclopropa[d]pyrazino[2,3-b]azepin-7-yl)-1H-1,2,3-triazole-4-carboxamide

The crude product was purified by Prep-TLC (ethyl acetate/hexane, 3/1)to afford the racemate. LC-MS (Method E): m/z=390.2 [M+H]⁺, 0.932 min.The racemate of5-benzyl-N-cis-5-methyl-6-oxo-5,6,7,7a,8,8a-hexahydro-cyclopropa[d]pyrazino[2,3-b]azepin-7-yl)-1H-1,2,3-triazole-2-carboxamide(50 mg, 0.129 mmol) was separated by Prep-Chiral-HPLC with the followingconditions: Column: CHIRALPAK IA, 2.12×15 cm, 5 μm; Mobile Phase A:Hexane, Mobile Phase B: IPA; Flow rate: 20 mL/min; Gradient: 50% B to50% B over 20 min; UV 254 & 220 nm; Rt1: 11.273; Rt2: 15.609 to affordthe title compound as the first eluting isomer: ¹H NMR (400 MHz,CD₃OD-d₄) δ 8.42-8.38 (m, 3H), 7.41-7.32 (m, 5H), 5.65 (s, 2H), 4.79 (s,1H), 3.40 (s, 3H), 2.64-2.57 (m, 1H), 2.26-2.20 (m, 1H), 1.54-1.49 (m,1H), 1.33-1.26 (m, 1H). LC-MS (Method J): m/z=390.1 [M+H]⁺, 1.162 min.

Example197:5-benzyl-N-((7S,7aS,8aR)-5-methyl-6-oxo-5,6,7,7a,8,8a-hexahydrocyclopropa[d]pyrazino[2,3-b]azepin-7-yl)isoxazole-3-carboxamide

The crude product was purified by Prep-TLC (ethyl acetate/hexane, 3/1)to afford the racemate. LC-MS (Method E): m/z=390.2 [M+H]⁺, 1.072 min.The racemate of5-benzyl-N-cis-5-methyl-6-oxo-5,6,7,7a,8,8a-hexahydro-cyclopropa[d]pyrazino[2,3-b]azepin-7-yl)-isoxazole-2-carboxamidewas separated by Prep-Chiral-HPLC with the following conditions: Column:CHIRALPAK IA, 2×25 cm, 5 μm; Mobile Phase A: Hexane:DCM=5:1, MobilePhase B: EtOH; Flow rate: 15 mL/min; Gradient: 50% B to 50% B in 24 min;UV 254 & 220 nm; Rt1: 15.4; Rt2: 19.4 to afford the title compound asthe first eluting isomer: ¹H NMR (400 MHz, CD₃OD-d₄) δ 8.42-8.38 (m,2H), 7.36-7.24 (m, 5H), 6.44 (s, 1H), 4.76 (s, 1H), 4.18 (s, 2H), 3.57(s, 3H), 2.64-2.57 (m, 1H), 2.24-2.17 (m, 1H), 1.53-1.48 (m, 1H),1.32-1.26 (m, 1H). LC-MS (Method D): m/z=390.0 [M+H]⁺, 1.747 min.

Example 198:5-benzyl-N-((7S,7aS,8aR)-5-methyl-6-oxo-5,6,7,7a,8,8a-hexahydrocyclopropa[d]pyrazino[2,3-b]azepin-7-yl)-1,3,4-thiadiazole-2-carboxamide

The crude product was purified by Prep-TLC (ethyl acetate/hexane, 3/1)to afford the racemate. LC-MS (Method E): m/z=407.1 [M+H]⁺, 1.017 min.

The racemate of5-benzyl-N-(cis-5-methyl-6-oxo-5,6,7,7a,8,8a-hexahydrocyclopropa[d]pyrazino[2,3-b]azepin-7-yl)-1,3,4-thiadiazole-2-carboxamidewas separated by Prep-Chiral-HPLC with the following conditions: Column:Chiralpak ID-2, 2×25 cm, 5 μm; Mobile Phase A: MTBE, Mobile Phase B:EtOH; Flow rate: 20 mL/min; Gradient: 30% B to 30% B over 26 min; UV 254& 220 nm; Rt1: 19.418; Rt2: 22.874 to afford the title compound as thefirst eluting isomer: ¹H NMR (400 MHz, CD₃OD-d₄) δ 8.41-8.37 (m, 2H),7.38-7.26 (m, 5H), 4.77 (s, 1H), 4.51 (s, 2H), 3.48 (s, 3H), 2.65-2.58(m, 1H), 2.28-2.22 (m, 1H), 1.56-1.50 (m, 1H), 1.34-1.27 (m, 1H). LC-MS(Method D): m/z=407.1 [M+H]⁺, 1.680 min.

Example 200:(S)-5-benzyl-N-(2,4-dimethyl-5-oxo-5,6,7,8-tetrahydro-4H-thiazolo[4,5-b]azepin-6-yl)-1,3,4-oxadiazole-2-carboxamide

The crude product was purified by Prep-TLC (ethyl acetate/petroleumether, 3/1) to afford the racemate. LC-MS (Method D): m/z=398.10 [M+H]⁺,1.284 min. The racemate of5-benzyl-N-(2,4-dimethyl-5-oxo-5,6,7,8-tetrahydro-4H-thiazolo[4,5-b]azepin-6-yl)-1,3,4-oxadiazole-2-carboxamidewas separated by Prep-Chiral-HPLC with the following conditions: Column:CHIRALPAK IA, 2.12×15 cm, 5 μm; Mobile Phase A: Hexane, Mobile Phase B:EtOH; Flow rate: 20 mL/min; Gradient: 50% B to 50% B over 13 min; UV 220& 254 nm; Rt1: 7.88; Rt2: 10.109 to afford the title compound as thefirst eluting isomer: ¹H NMR (400 MHz, CD₃OD-d₄) δ 7.41-7.24 (m, 5H),4.65 (dd, J=11.5, 6.7 Hz, 1H), 4.33 (s, 2H), 3.36 (s, 3H), 3.06-2.84 (m,2H), 2.72-2.54 (m, 4H), 2.46-2.33 (m, 1H). LC-MS (Method D): m/z=398.10[M+H]⁺, 1.283 min.

Example 201:(S)-1-benzyl-N-(5-methyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepin-3-yl)-1H-1,2,3-triazole-4-carboxamide

The crude product was purified by column chromatography (ethylacetate/petroleum ether, 2/1) to afford the title compound: ¹H NMR (400MHz, CD₃OD-d₄) δ 8.41-8.33 (m, 2H), 7.68 (dd, J=8.1, 1.6 Hz, 1H),7.45-7.28 (m, 6H), 5.66 (s, 2H), 5.04 (dd, J=11.6, 7.2 Hz, 1H), 4.69(dd, J=9.9, 7.2 Hz, 1H), 4.54 (dd, J=11.6, 9.8 Hz, 1H), 3.49 (s, 3H).LC-MS (Method D): m/z=379.1 [M+H]⁺, 1.239 min.

Example 203:1-benzyl-N-((2R,3S)-2,5-dimethyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepin-3-yl)-1H-1,2,3-triazole-4-carboxamide

The crude product was purified by Prep-HPLC with the followingconditions: Column: Xbridge Prep C18, 5 μm, 19×150 mm; Mobile Phase A:Water (0.1% NH₄HCO₃), Mobile Phase B: MeCN; Flow rate: 20 mL/min;Gradient: 25% B to 66% B over 8 min; UV 254 & 220 nm; Rt: 6.68 min toafford the title compound. ¹H NMR (300 MHz, CD₃OD-d₄) δ 8.27 (s, 1H),8.23-8.20 (m, 1H), 7.56 (dd, J=8.0, 1.6 Hz, 1H), 7.29-7.17 (m, 6H), 5.54(s, 2H), 4.97-4.85 (m, 2H), 3.38 (s, 3H), 1.31 (d, J=6.2 Hz, 3H). LC-MS(Method Q): m/z=393.2 [M+H]⁺, 1.354 min.

Example 204:2-benzyl-N-((2R,3S)-2,5-dimethyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepin-3-yl)-2H-1,2,3-triazole-4-carboxamide

The crude product was purified by Prep-HPLC with the followingconditions: Column: Xbridge Prep C18, 5 μm, 19×150 mm; Mobile Phase A:Water (0.1% NH₄HCO₃), Mobile Phase B: MeCN; Flow rate: 20 mL/min;Gradient: 35% B to 72% B over 8 min; UV 254 & 220 nm; Rt: 5.95 min toafford the title compound. ¹H NMR (300 MHz, CD₃OD-d₄) δ 8.32 (dd, J=4.7,1.5 Hz, 1H), 8.06 (s, 1H), 7.68 (dd, J=8.0, 1.6 Hz, 1H), 7.40-7.27 (m,6H), 5.70 (s, 2H), 5.09-4.97 (m, 2H), 3.49 (s, 3H), 1.41 (d, J=6.1 Hz,3H). LC-MS (Method D): m/z=393.10 [M+H]⁺, 1.479 min.

Example 205:1-benzyl-N-((3S,4R)-1-trideuteriomethyl-4-methyl-2-oxo-1,2,3,4-tetrahydropyrido[2,3-b][1,4]oxazepin-3-yl)-4-fluoro-1H-pyrazole-3-carboxamide

The crude product was purified by Prep-HPLC with the followingconditions: Column: Kinetex 5 μm EVO C18 OBD Column, 21.2×150 mm, 5 μm;Mobile Phase A: Water (0.1% formic acid), Mobile Phase B: MeCN; Flowrate: 25 mL/min; Gradient: 30% B to 60% B over 8 min; UV 254 & 220 nm;Rt: 7.52 min to afford the title compound: ¹H NMR (400 MHz, CD₃OD-d₄) δ8.23 (dd, J=4.8, 1.6 Hz, 1H), 7.94 (dd, J=8.0, 2.0 Hz, 1H), 7.77 (d,J=4.4 Hz, 1H), 7.46-7.32 (m, 6H), 5.35 (s, 2H), 5.18-5.07 (m, 2H), 1.45(d, J=6.0 Hz, 3H). LC-MS (Method O): m/z=413.2 [M+H]⁺, 1.472 min.

Example 206:1-benzyl-N-((1aS,2S,8bR)-7-cyano-4-trideuteriomethyl-3-oxo-1,1a,2,3,4,8b-hexahydrobenzo[b]cyclopropa[d]azepin-2-yl)-4-fluoro-1H-pyrazole-3-carboxamide

The crude product was purified by Prep-TLC (ethyl acetate/hexane, 3/1)to afford the racemate. LC-MS (Method C): m/z=433.1 [M+H]⁺, 1.078 min.The racemate of1-benzyl-N-(cis-7-cyano-4-trideuteriomethyl-3-oxo-1,1a,2,3,4,8b-hexahydrobenzo[b]cyclopropa[d]azepin-2-yl)-4-fluoro-1H-pyrazole-3-carboxamidewas separated by Prep-Chiral-HPLC with the following conditions: Column:CHIRALPAK IA, 2.12×15 cm, 5 μm; Mobile Phase A: Hexane, Mobile Phase B:EtOH; Flow rate: 20 mL/min; Gradient: 50% B to 50% B over 18 min; UV 254& 220 nm; Rt1: 8.283; Rt2: 14.011 to afford the title compound as thesecond eluting isomer: ¹H NMR (400 MHz, DMSO-d₆) δ 8.15 (d, J=4.4 Hz,1H), 8.09 (d, J=6.8 Hz, 1H), 8.05 (d, J=2.0 Hz, 1H), 7.77 (dd, J=8.4,2.0 Hz, 1H), 7.45 (d, J=8.4 Hz, 1H), 7.41-7.28 (m, 5H), 5.35 (s, 2H),4.46 (d, J=6.8 Hz, 1H), 2.39-2.32 (m, 1H), 2.03-1.96 (m, 1H), 1.19-1.14(m, 1H), 1.12-1.08 (m, 1H). LC-MS (Method D): m/z=433.2 [M+H]⁺, 1.321min.

Example 209:(S)-4-fluoro-N-(5-methyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepin-3-yl)-1-(oxazol-4-ylmethyl)-1H-pyrazole-3-carboxamide

The crude product was purified by Prep-HPLC with the followingconditions: Column: Xbridg Prep C18; 19×150 mm; 5 μm; Mobile Phase A:Water (0.1% NH₄HCO₃), Mobile Phase B: MeCN; Flow rate: 20 mL/min;Gradient: 21% B to 25% B over 10 min; UV 254 & 220 nm to afford thetitle compound: ¹H NMR (300 MHz, DMSO-d₆) δ 8.40 (d, J=0.6 Hz, 1H), 8.36(dd, J=4.8, 1.5 Hz, 1H), 8.23 (d, J=7.8 Hz, 1H), 8.19 (d, J=0.9 Hz, 1H),8.04 (d, J=4.5 Hz, 1H), 7.70 (dd, J=7.8, 1.5 Hz, 1H), 7.33 (dd, J=8.1,4.8 Hz, 1H), 5.28 (s, 2H), 4.89-4.78 (m, 1H), 4.67 (dd, J=11.4, 9.9 Hz,1H), 4.50 (dd, J=9.6, 7.5 Hz, 1H), 3.35 (s, 3H). LC-MS (Method T):m/z=387.2 [M+H]⁺, 0.973 min.

Example 213:(S)—N-(5-methyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepin-3-yl)-5-(pyridin-2-ylmethyl)thiazole-2-carboxamide

The title compound was prepared according to the methods describedherein using the appropriate starting material. The crude product waspurified by Prep-TLC (ethyl acetate/petroleum ether, 3/1) to afford thetitle compound: ¹H NMR (400 MHz, CD₃OD-d₄) δ 8.51-8.48 (m, 1H), 8.33(dd, J=4.8, 1.6 Hz, 1H), 7.84-7.77 (m, 2H), 7.66 (dd, J=8.0, 1.6 Hz,1H), 7.44-7.38 (m, 1H), 7.34-7.27 (m, 2H), 4.97 (dd, J=11.5, 7.2 Hz,1H), 4.67 (dd, J=9.9, 7.2 Hz, 1H), 4.52 (dd, J=11.5, 9.9 Hz, 1H), 4.40(s, 2H), 3.47 (s, 3H). LC-MS (Method D): m/z=396.0 [M+H]⁺, 1.786 min.

Example 214:(S)-4-fluoro-1-((5-fluoropyridin-2-yl)methyl)-N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-pyrazole-3-carboxamide

The crude product was purified by Prep-HPLC with the followingconditions: Column: Gemini-NX/5 u, C18 150×21.2 mm; Mobile Phase A:Water (10 mmol/L NH₄HCO₃), Mobile Phase B: MeCN; Flow rate: 20 mL/min;Gradient: 45% B to 50% B over 8 min; UV 254 & 220 nm; Rt: 7.33 to affordthe title compound: ¹H NMR (300 MHz, CD₃OD-d₄) δ 8.45 (d, J=3.0 Hz, 1H),7.84 (d, J=4.5 Hz, 1H), 7.65-7.58 (m, 1H), 7.44-7.20 (m, 5H), 5.43 (s,2H), 4.97 (dd, J=11.4, 7.5 Hz, 1H), 4.56 (dd, J=9.9, 7.5 Hz, 1H), 4.37(dd, J=11.4, 9.9 Hz, 1H), 3.41 (s, 3H). LC-MS (Method D): m/z=414.1[M+H]⁺, 1.579 min.

Example 215:(S)-5-benzyl-N-(5-methyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepin-3-yl)-1,2,4-oxadiazole-3-carboxamide

The residue was purified by Prep-HPLC with the following conditions:Column: Xbridge Prep C18, 5 μm, 19×150 mm; Mobile Phase A: Water (0.1%NH₄HCO₃), Mobile Phase B: MeCN; Flow rate: 20 mL/min; Gradient: 30% B to60% B over 8 min; UV 254 & 220 nm; Rt: 6.65 min to afford the titlecompound: ¹H NMR (300 MHz, CD₃OD-d₄) δ 8.36-8.31 (m, 1H), 7.69-7.63 (m,1H), 7.40-7.26 (m, 6H), 5.07-4.97 (m, 1H), 4.71-4.62 (m, 1H), 4.60-4.49(s, 1H), 4.38 (s, 2H), 3.47 (s, 3H). LC-MS (Method D): m/z=380.1 [M+H]⁺,1.322 min.

Example 216:(S)-1-((5-chloropyridin-2-yl)methyl)-4-fluoro-N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-pyrazole-3-carboxamide

The residue was purified by Prep-HPLC with the following conditions:Column: Gemini-NX/5 u, C18 150×21.2 mm; Mobile Phase A: Water (10 mmol/LNH₄HCO₃), Mobile Phase B: MeCN; Flow rate: 20 mL/min; Gradient: 40% B to55% B over 8 min; UV 254 & 220 nm; Rt: 6.73 min to afford the titlecompound: ¹H NMR (300 MHz, CD₃OD-d₄) δ 8.51 (d, J=2.4 Hz, 1H), 7.82 (dd,J=8.4, 3.6 Hz, 2H), 7.42-7.35 (m, 1H), 7.32-7.17 (m, 4H), 5.40 (s, 2H),4.94 (dd, J=11.4, 7.5 Hz, 1H), 4.54 (dd, J=9.9, 7.5 Hz, 1H), 4.34 (dd,J=11.7, 10.2 Hz, 1H), 3.37 (s, 3H). LC-MS (Method D): m/z=430.1 [M+H]⁺,1.673 min.

Example217:5-benzyl-N-((2R,3S)-2,5-dimethyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepin-3-yl)-1,3,4-thiadiazole-2-carboxamide

The crude product obtained using Amide Coupling Procedure C was purifiedby Prep-HPLC with the following conditions: Column: Gemini-NX/5 u, C18150×21.2 mm; Mobile Phase A: Water (10 mmol/L NH₄HCO₃), Mobile Phase B:MeCN; Flow rate: 20 mL/min; Gradient: 55% B to 80% B over 6 min; UV 254& 220 nm; Rt: 4.60 min to afford the title compound. ¹H NMR (300 MHz,CD₃OD-d₄) δ 8.34-8.25 (m, 1H), 7.70-7.66 (m, 1H), 7.39-7.25 (m, 6H),5.11-4.96 (m, 2H), 4.51 (s, 2H), 3.50 (s, 3H), 1.42 (d, J=6.0 Hz, 3H).LC-MS (Method D): m/z=410.0 [M+H]⁺, 1.725 min.

Example 218:5-benzyl-N-((1aS,2S,8bR)-7-cyano-4-methyl-3-oxo-1,1a,2,3,4,8b-hexahydrocyclopropa[d]pyrido[2,3-b]azepin-2-yl)-4H-1,2,4-triazole-3-carboxamide

The crude product was purified by Prep-TLC (ethyl acetate/hexane, 3/1)to afford the racemate. LC-MS (Method D): m/z=414.1 [M+H]⁺, 1.222 min.The racemate of5-benzyl-N-(cis-7-cyano-4-methyl-3-oxo-1,1a,2,3,4,8b-hexahydrocyclopropa[d]pyrido[2,3-b]azepin-2-yl)-4H-1,2,4-triazole-3-carboxamidewas separated was separated by Prep-Chiral-HPLC with the followingconditions: Column: CHIRAL ART Cellulose-SB, 2×25 cm, 5 μm; Mobile PhaseA: MTBE, Mobile Phase B: EtOH; Flow rate: 20 mL/min; Gradient: 20% B to20% B over 16 min; UV 254 & 220 nm; Rt1: 7.89; Rt2: 8.598 to afford thetitle compound as the second eluting isomer: ¹H NMR (400 MHz, CD₃OD-d₄)δ 8.71 (d, J=2.4 Hz, 1H), 8.32 (d, J=2.0 Hz, 1H), 7.37-7.25 (m, 5H),4.73 (s, 1H), 4.20 (s, 2H), 3.44 (s, 3H), 2.40-2.33 (m, 1H), 2.21-2.14(m, 1H), 1.46-1.41 (m, 1H), 1.34-1.26 (m, 1H). LC-MS (Method D):m/z=414.1 [M+H]⁺, 1.221 min.

Example 219:(S)-5-(3-cyanobenzyl)-N-(9-methyl-8-oxo-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]azepin-7-yl)thiazole-2-carboxamide

The crude product obtained using Amide Coupling Procedure C was purifiedby Prep-TLC (ethyl acetate/petroleum ether, 3/1) to afford the racemate.LC-MS (Method S): m/z=418.1 [M+H]⁺, 1.025 min. The racemate of5-(3-cyanobenzyl)-N-(9-methyl-8-oxo-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]azepin-7-yl)thiazole-2-carboxamidewas separated by Prep-Chiral-HPLC with the following conditions: Column:(R,R)Whelk-O1, 21.1×250 mm, 5 μm; Mobile Phase A: Hexane:Dichloromethane=4.5: 1, Mobile Phase B: EtOH; Flow rate: 20 mL/min;Gradient: 70% B to 70% B over 23 min; UV 254 & 220 nm; Rt1: 12.88; Rt2:18.81 to afford the title compound as the first eluting isomer: ¹H NMR(400 MHz, CD₃OD-d₄) δ 8.44 (dd, J=4.8, 1.6 Hz, 1H), 7.81 (dd, J=7.6, 1.6Hz, 1H), 7.77 (s, 1H), 7.69 (s, 1H), 7.66-7.61 (m, 2H), 7.55-7.51 (m,1H), 7.31-7.27 (m, 1H), 4.52-4.46 (m, 1H), 4.35 (s, 2H), 3.48 (s, 3H),2.94-2.79 (m, 2H) 2.69-2.58 (m, 1H), 2.34-2.24 (m, 1H). LC-MS (MethodD): m/z=418.0 [M+H]⁺, 1.716 min.

Example 220:(S)-4-fluoro-1-((6-methoxypyridin-2-yl)methyl)-N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-pyrazole-3-carboxamide

The crude product was purified by Prep-HPLC with the followingconditions: Column: Gemini-NX/5 u, C18 150×21.2 mm; Mobile Phase A:Water (10 mmol/L NH₄HCO₃), Mobile Phase B: MeCN; Flow rate: 20 mL/min;Gradient: 40% B to 50% B over 8 min; UV 254 & 220 nm; Rt: 8.07 min toafford the title compound. ¹H NMR (300 MHz, CD₃OD-d₄) δ 7.85 (d, J=4.5Hz, 1H), 7.63 (dd, J=8.1, 7.2 Hz, 1H), 7.43-7.40 (m, 1H), 7.39-7.20 (m,3H), 6.78 (d, J=7.2, 1H), 6.71 (d, J=8.4, 1H), 5.32 (s, 2H), 4.98 (dd,J=11.4, 7.5 Hz, 1H), 4.58 (dd, J=9.9, 7.5 Hz, 1H), 4.37 (dd, J=11.4, 9.9Hz, 1H), 3.86 (s, 3H), 3.40 (s, 3H). LC-MS (Method D): m/z=426.2 [M+H]⁺,1.755 min.

Example 221:5-(difluoro(phenyl)methyl)-N-((2R,3S)-2,5-dimethyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepin-3-yl)-1,3,4-oxadiazole-2-carboxamide

The crude product was purified by Prep-HPLC with the followingconditions: Column: Gemini-NX/5 u, C18 150×21.2 mm; Mobile Phase A:Water (10 mmol/L NH₄HCO₃), Mobile Phase B: MeCN; Flow rate: 20 mL/min;Gradient: 47% B to 60% B over 10 min; UV 254 & 220 nm; Rt: 8.82 min toafford the title compound. ¹H NMR (300 MHz, CD₃OD-d₄) δ 8.33 (dd, J=4.8,1.8 Hz, 1H), 7.69-7.66 (m, 3H), 7.62-7.53 (m, 3H), 7.32 (dd, J=8.1, 4.8Hz, 1H), 5.08-4.93 (m, 2H), 3.50 (s, 3H), 1.44 (d, J=6.3 Hz, 3H). LC-MS(Method O): m/z=430.1 [M+H]⁺, 1.679 min.

Example 222:5-benzyl-N-((2R,3S)-2,5-dimethyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepin-3-yl)-1,2,4-oxadiazole-3-carboxamide

The crude product was purified by Prep-HPLC with the followingconditions: Column: Xbridge Prep C18, 5 μm, 19×150 mm; Mobile Phase A:Water (0.1% NH₄HCO₃), Mobile Phase B: MeCN; Flow rate: 20 mL/min;Gradient: 40% B to 70% B over 8 min; UV 254 & 220 nm; Rt: 5.87 min toafford the title compound. ¹H NMR (300 MHz, CD₃OD-d₄) δ 8.35-8.31 (m,1H), 7.71-7.66 (m, 1H), 7.41-7.27 (m, 6H), 5.10-4.97 (m, 2H) 4.39 (s,2H), 3.49 (s, 3H), 1.40 (d, J=6.2 Hz, 3H). LC-MS (Method D): m/z=394.1[M+H]⁺, 2.709 min.

Example 223:5-(4-fluorobenzyl)-N-((7S,7aS,8aR)-5-methyl-6-oxo-5,6,7,7a,8,8a-hexahydrocyclopropa[d]pyrazino[2,3-b]azepin-7-yl)-1,3,4-oxadiazole-2-carboxamide

The crude product was purified by Prep-TLC (ethyl acetate/petroleumether, 3/1) to afford the racemate. LC-MS (Method D): m/z=409.05 [M+H]⁺,1.255 min. The racemate of5-(4-fluorobenzyl)-N-cis-5-methyl-6-oxo-5,6,7,7a,8,8a-hexahydrocyclopropa[d]pyrazino[2,3-b]azepin-7-yl)-1,3,4-oxadiazole-2-carboxamidewas separated by Prep-Chiral-HPLC with the following conditions: Column:CHIRALPAK IE, 2×25 cm, 5 μm; Mobile Phase A: MTBE, Mobile Phase B: EtOH;Flow rate: 20 mL/min; Gradient: 30% B to 30% B in 16 min; UV 254 & 220nm; Rt1: 10.514; Rt2: 13.482 to afford the title compound as the firsteluting isomer: ¹H NMR (400 MHz, CDCl₃-d) δ 8.49-8.32 (m, 3H), 7.39-7.28(m, 2H), 7.14-6.94 (m, 2H), 4.85 (d, J=7.0 Hz, 1H), 4.25 (s, 2H), 3.45(s, 3H), 2.71-2.62 (m, 1H), 2.30-2.21 (m, 1H), 1.57-1.50 (m, 1H),1.30-1.22 (m, 1H). LC-MS (Method V): m/z=409.05 [M+H]⁺, 2.450 min.

Example 224:(S)-4-fluoro-N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1-(pyrimidin-2-ylmethyl)-1H-pyrazole-3-carboxamide

The crude product was purified by the Prep-HPLC with the followingconditions: Column: Xbridge Prep C18, 5 μm, 19×150 mm; Mobile Phase A:Water (0.1% NH₄HCO₃), Mobile Phase B: MeCN; Flow rate: 20 mL/min;Gradient: 16% B to 43% B over 8 min; UV 254 & 220 nm; Rt: 7.47 min toafford the title compound. ¹H NMR (300 MHz, CD₃OD-d₄) δ 8.81-8.77 (m,2H), 7.91-7.87 (m, 1H), 7.48-7.41 (m, 2H), 7.38-7.21 (m, 3H), 5.58 (s,2H), 5.03-4.95 (m, 1H), 4.62-4.56 (m, 1H), 4.43-4.34 (m, 1H), 3.42 (s,3H). LC-MS (Method D): m/z=397.0 [M+H]⁺, 2.334 min.

Example 225:(S)-5-benzyl-N-(1-methyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-3-yl)-1,3,4-oxadiazole-2-carboxamide

¹H NMR (300 MHz, CD₃OD-d₄) δ 7.47-7.18 (m, 9H), 4.47 (dd, J=11.7, 7.9Hz, 1H), 4.31 (s, 2H), 3.40 (s, 3H), 2.93-2.82 (m, 1H), 2.73 (dd,J=13.6, 6.8 Hz, 1H), 2.52-2.43 (m, 1H), 2.33-2.21 (m, 1H). LC-MS (MethodD): m/z=377.0 [M+H]⁺, 1.732 min.

The other compounds of Table 1 were, or can be, prepared according tothe Examples above and/or general procedures described herein using theappropriate starting materials.

Biological Assays

Compounds were tested for binding and cellular kinase activity accordingto the following protocols. proGST-hRIPK1 (8-327) enzyme was generatedby Proteros GmbH by Baculovirus expression system.

The cellular necroptosis assay (Cell IC₅₀ in Tables 5-7) evaluates theability of compounds to reverse the necrosis induced by human TNFα. Tenconcentrations of the test compounds were assessed in duplicate in twodifferent test occasions. FADD-deficient Jurkat cells were purchasedfrom ATCC (ATCC-CRL-2572) and cultured in suspension in RPMI mediumsupplemented with 10% heat inactivated of FBS and 1% Pen-Strep. The dayof the experiment cells were diluted to a density of 0.12×10⁵ cells/mL(5,000 cells/well) with culture medium and added (40 μL) into the384-well plate containing 0.2 μL/well of test compounds and referencecompounds (CRCs) (200×). Cell plates were then incubated at 37° C.—5%CO₂. After 30 min, necroptotic cell death was induced with human TNFα(10 ng/mL) and cell viability was evaluated 48 h later by measuringcellular ATP levels using CellTiter-Glo® kit (Promega). Luminescence wasread by using Victor V (Perkin Elmer) multilabel plate reader. Data wereexpressed as % of max viability calculated comparing the values to TNFαuntreated control cells which represents 100% of cell viability. CRCswere analysed by Dotmatics and IC₅₀ values were calculated by non-linearregression using 4 parameter-logistic equation.

Fluorescent Polarization Binding (FP Binding) assay (Berger S. B. et al.(2015) Cell Death Discovery, 1: 15009; Maki J. L. et al. (2012) AnalBiochem., 427(2): 164-174) was performed in polystyrene low volume384-well black plate, at Room Temperature (RT) in a final volume of 10.1μl/well using 10 nM of GST-hRIPK1 (8-327) enzyme and 5 nM offluorescent-labeled ligand(14-(2-{[3-({2-{[4-(cyanomethyl)phenyl]amino}-6-[(5-cyclopropyl-1H-pyrazol-3-yl)amino]-4-pyrimidinyl}amino)propyl]amino}-2-oxoethyl)-16,16,18,18-tetramethyl-6,7,7a,8a,9,10,16,18-octahydrobenzo[2″,3″]indolizino[8″,7″:5′,6′]pyrano[3′,2′:3,4]pyrido[1,2-a]indol-5-ium-2-sulfonate.

Test Compounds were serially diluted in DMSO at 100 fold finalconcentrations in the assay (1% DMSO final). In each well of a 384-wellPlate were dispensed 0.1 μL of compound solution (or DMSO for controls)followed by 5 μL of GST-hRIPK1 (8-327) at twice the final concentrationsin assay buffer (50 mM HEPES pH 7.5, 10 mM NaCl, 50 mM MgCl₂, 0.02%CHAPS, 0.5 mM DTT and 0.01% Pluronic F127). For negative control theenzyme addition was replaced by assay buffer only.

After addition of 5 μL of fluorescent-labeled ligand at twice the finalconcentrations in assay buffer, the plate was incubated at RT for 30min. At the end, the binding was measured as FP value with the Envision(PerkinElmer) plate reader using filter for an excitation λ=531 nm FPand an emission λ=595 nm FP (S & P-pol).

GST-hRIPK1 (8-327) enzyme was generated by Proteros GmbH by Baculovirusexpression system.

Test compounds were diluted in DMSO and 0.1 μL of solution was dispensedto each well of a 384-well white solid microplate. The assay buffer was50 mM HEPES pH 7.5, 50 mM NaCl, 30 mM MgCl₂. The buffer was supplementedwith 0.02% CHAPS, 0.01% of Pluronic F127, 0.1 mg/mL BSA and 1 mM DTT.MnCl₂, 5 mM, was included in the assay buffer on the day of theexperiment. The enzymatic reaction comprised 1.5 μg/mL GST-hRIPK1(8-327) and 50 μM ATP for receptor interacting protein kinase 1 and 15μM ATP. 5 μL of enzyme and 5 μL of ATP were added to the plate at twicethe final assay concentration and incubated at room temperature for 3hours. Following this reaction, 10 μL of ADP-Glo reagent (Promega) wasadded to each well and incubated for 40 min at room temperature. Thisstops the kinase reaction and depletes any remaining ATP. 20 μL ofADP-Glo detection reagent was then added to each well and incubated atroom temperature for at least 15 minutes. The detection reagent convertsADP to ATP and introduces luciferase and luciferin to detect ATP. Theluminescence is then measured with the Envision (PerkinElmer) platereader. Test compound inhibition was expressed as percent inhibition ofinternal assay controls. For concentration response curves, normalizeddata is fit and IC₅₀ determined using XL-fit (IDBS) for Excel. The ICwere averaged to determine a mean value, for a minimum of twoindependent experiments.

Test compound inhibition was expressed as percent inhibition of internalassay controls. For concentration response curves, normalized data isfit and IC₅₀ determined using XL-fit (IDBS) for Excel. The IC₅₀ wereaveraged to determine a mean value, for a minimum of two independentexperiments.

receptor-interacting protein kinase 1 cellular activity and binding ofexemplary compounds was determined according to the above generalprocedure. Results are summarized in Table 5. In the table below,activity is provided as follows: +++=0.0001 μM<IC₅₀<1 μM; ++=1μM<IC₅₀<10 μM; +=10 μM<IC₅₀; ++*=3 μM<IC₅₀.

TABLE 5 ADP FP IC₅₀ IC₅₀ Cell IC₅₀ Compound (μM) (μM) (μM) 1A +++ +++ 1B+++ 2 +++ +++ +++ 2A +++ +++ 2B +++ +++ 3 +++ +++ 4 +++ +++ 5 +++ +++ 6+++ +++ 7 +++ +++ 7A +++ +++ 7B + ++ 8 +++ +++ 9 +++ +++ 10 +++ +++ 11+++ +++ 11A +++ +++ 11B ++ +++ 12 +++ +++ 12A +++ +++ 12B +++ +++ 13 +++14 +++ 15 + 16 + 17 + 18 + 19 ++ 20 ++ 21 + 22 + 23 + 24 + 25 + 26 +27 + 30 +++ +++ 32 +++ +++ 33 + 35 +++ +++ 38A +++ +++ 38B ++* 41 ++++++ 42 +++ +++ 43 ++ 44 +++ +++ 45 +++ +++ 46A +++ +++ 46B ++* 49 ++ 50A+++ 50B ++ 51 +++ +++ 52 +++ +++ 54A +++ +++ 54B +++ +++ 55 +++ +++ 56+++ +++ 57 +++ +++ 58 +++ +++ 59 +++ +++ 60 60A +++ +++ 60B ++* 61 ++++++ 62 +++ +++ 63 +++ +++ 64 +++ +++ 65 + 66 +++ +++ 67A +++ 67B ++* 68A+++ +++ 68B ++* 69A +++ +++ 69B ++* 70A +++ +++ 70B ++* 71A +++ +++ 71B++* 72 +++ +++ 73 +++ +++ 74 +++ +++ 75A +++ +++ 75B ++* 76 +++ +++ 77+++ +++ 78 +++ +++ 79 +++ +++ 80A +++ +++ 80B ++* 81A +++ +++ 81B ++*82A +++ +++ 82B ++* 83A +++ +++ 83B ++ 84 +++ +++ 85 +++ +++ 86 +++ +++87 +++ 88 ++* ++ 89A ++ 89B +++ +++ 90A ++ 90B +++ +++ 91 +++ 92 +++ +++93 +++ 94 +++ +++ 95 ++* 96 +++ +++ 98A ++* 98B +++ 99 ++ +++ 100A ++++++ 100B +++ 101A ++* 101B +++ +++ 102A ++ 102B +++ 103A ++* 103B ++++++ 104A ++* 104B +++ 105A +++ +++ 105B ++* 106 +++ 107A ++* 107B ++++++ 108 +++ 109A +++ +++ 109B ++* 110A ++* 110B +++ +++ 111A ++ 111B ++++++ 112 +++ +++ 113 +++ 114A +++ +++ 114B ++* 115 +++ +++ 116 +++ +++117 +++ +++ 118A ++* 118B ++ 119A ++* 119B +++ 120A +++ +++ 120B ++*121A ++* 121B +++ 122 +++ +++ 123 +++ 124 +++ +++ 125A ++* 125B +++ +++126 +++ +++ 127 +++ 128 +++ +++ 129A +++ 129B ++* 130 +++ +++ 131A +++131B ++* 132 +++ +++ 133 +++ +++ 134 +++ +++ 135 +++ +++ 136 +++ +++ 137+++ +++ 138 +++ +++ 139 +++ +++ 140 +++ +++ 141A ++* 141B +++ 142 ++++++ 143 +++ +++ 144 +++ +++ 145A +++ +++ 145B ++* 146 +++ +++ 147 ++++++ 148A +++ +++ 148B ++ 149 +++ +++ 150 +++ +++ 151 +++ +++ 152A ++*152B +++ +++ 153 +++ +++ 154A ++* 154B +++ +++ 155 +++ 156A ++* 156B ++++++ 157A ++* 157B +++ +++ 158 +++ +++ 159 +++ 160A +++ +++ 160B ++* 161+++ +++ 162 +++ +++ 163 +++ +++ 164 +++ +++ 165 +++ +++ 166 +++ +++ 167+++ +++ 168 +++ +++ 169 +++ +++ 170A +++ +++ 170B ++* 171 +++ +++ 172+++ +++ 173 +++ +++ 174 +++ +++ 175 +++ +++ 176 +++ 177A +++ +++ 177B++* 178A +++ +++ 178B ++* 179A +++ +++ 179B ++* 180A +++ +++ 180B ++*181A ++* 181B +++ +++ 182A ++* 182B +++ +++ 183A ++* 183B +++ +++ 184+++ 188 +++ +++ 190 +++ 192 +++ +++ 193 +++ +++ 194 +++ 195 +++ +++ 197+++ +++ 198 +++ +++ 200 +++ +++ 201 +++ +++ 203 +++ +++ 204 +++ 205 +++206 +++ +++ 207 ++* 208 +++ 209 +++ +++ 213 +++ 214 +++ +++ 215 +++ +++216 +++ +++ 217 +++ +++ 218 +++ +++ 219 +++ +++ 220 +++ +++ 221 +++ +++222 +++ +++ 223 +++ +++ 224 +++ +++ +++ 225 +++ 226 +++ 227 +++

TABLE 6 Human Rat Dog Cyno Cell hepatocyte unbound unbound unbound IC₅₀CL_(hep) Avg ER CL CL CL Compound (μM) (mL/min/kg) MDR1 (mL/min/kg)(mL/min/kg) (mL/min/kg) 119B 0.002 0 18 20 26 161 0.002 0 163 0.001 0 420.0006 0.8 19 22 64 42 83A 0.002 1.0 29 116 82 170A 0.003 3.1 177A 0.0024.2 1.4 55 58 146 0.0007 4.2 1.0 61 39 94 0.006 4.9 14 44 40 171 0.00075.1 19 32 172 0.001 5.3 65 183B 0.0008 5.3 36 66 0.012 6.3 1.6 113 36116 195 0.016 7.1 198 0.020 8.5 134 0.003 9.0 1.1 100 140 75A 0.003 9.124 91 93 205 0.021 11 148A 0.0007 12 197 0.003 13 46A 0.002 16 16 188142 0.0007 16 77 0.001 19 0.6 595 8 0.004 19 0.8 3700 9 0.008 19 920.0007 1.4 420 193 0.21

TABLE 7 Comparative Compounds Human Rat Dog Cyno Cell hepatocyte unboundunbound unbound IC₅₀ CL_(hep) Avg ER CL (mL/ CL (mL/ CL (ml/ Structure(μM) (mL/min/kg) MDR1 min/kg) min/kg) min/kg) A

0.0005  6.8 6.4 77 240 117 B

0.0003 14 1.0 C

0.001 19 0.9

The comparative compounds in Table 7 were prepared as described inExamples 12, 146, and 77, respectively, of WO 2014/125444.

The in vivo efficacy of compounds can be determined in mice using aTNF-driven systemic inflammatory response syndrome model as described byDuprez et. al. (2011, Immunity 35(6), 908-918) and Berger et. al. (2015,Cell Death Disc. 1, 15009). In this model system TNF/zVAD (tumornecrosis factor/Z-Val-Ala-DL-Asp-fluoromethylketone, a caspaseinhibitor) treatment results in temperature loss and the production ofseveral inflammatory cytokines. The ability of a test compound toinhibit these inflammatory effects can be measured in this model bydosing mice with test compound 15 minutes before administration ofTNF/zVAD and measuring the inflammatory response. The dose required toinhibit the inflammatory response is a measure of the compounds efficacyat that dose. Using this model, Compound 42 was orally pre-dosed at 5mg/kg 15 minutes before intraveneous administration of TNF/zVAD andtemperature loss in the mice was measured by an implanted temperaturechip. Treatment of mice with 5 mg/kg of Compound 42 resulted in 96%inhibition of temperature loss when compared to TNF/zVAD vehicle treatedanimals. In comparison, WO 2014/125444 discloses in Table 2 that Example12, corresponding to Example A of Table 7 above, required a dose of 30mg/kg to achieve 93% inhibition. The decrease in dosing has a number ofimportant potential advantages, including requiring less frequentadministration to a patient, increased patient compliance, and improvedsafety profile such as lower toxicities while achieving similarefficacy.

Based on the known crystal structure of comparative Example C andreceptor-interacting protein kinase 1 (Harris et al. J. Med. Chem.,2016, 59 (5), pg. 2163-2178), the phenyl carbon atom adjacent to theazepinone moiety (i.e., X⁹ of the formulas disclosed herein) interactswith a lipophilic pocket of receptor-interacting protein kinase 1.

Certain compounds were found to have significantly improved metabolicstability when X⁹ of the formulas disclosed herein is a N atom ascompared to a carbon atom. For instance, Compound 42, in comparison tocomparative Example A, when tested according to the assay describedbelow, was found to have an average human hepatocyte clearance of 0.8mL/min/kg versus 6.8 mL/min/kg for comparative Example A. As describedin the metabolic stability section below, a CL_(hep) of 6.8 mL/min/kgcorresponds to a clearance of approximately 32% of liver blood flow,whereas for Compound 42, a CL_(hep) value of 0.8 mL/min/kg correspondsto a clearance of less than 4% of liver blood flow, demonstrating thesignificant improvement in stability for compounds when X⁹ is a N atom.From the data presented above, it will be apparent to those skilled inthe art that compounds with lower human CL_(hep) values should allow forlower human clinical doses, less frequent administration to a patient,increased patient compliance, and improved safety profile such as lowertoxicities.

MDCKII-MDR1 Permeability

The blood brain barrier (BBB) separates circulating blood from theextracellular fluid of the central nervous system (CNS). The passivemembrane permeability (Papp) and the P-gp (P-glycoprotein) substrateefflux potential were determined using the MDCKII-MDR1 cell line as anin vitro model of the effective permeability of a compound through theBBB. A bidirectional assay (Apical to Basolateral (A->B) and Basolateralto Apical (B->A)), in the absence and in the presence of GF120918 (aP-gp inhibitor) was conducted using pre-plated MDCKII-MDR1 cells(Corning HTS Transwell-96) obtained from SOLVO Biotechnology. The assaywas run at 3 μM for 90 min (minutes) in triplicate using a HBSS+12.5 mMHEPES pH 7.4 transport buffer. Following incubation of samples fromdonor and receiver, wells were removed and measured by LC-MS/MS. Sampleswere extracted by protein precipitation with acetonitrile containing anappropriate internal standard (IS) having a known mass and molecularweight. The precipitate was centrifuged for 10 min at 3000 rpm(revolutions per minute). The supernatants were then collected, dilutedif necessary, and injected on to the LC-MS/MS system. Specificparent/daughter ion pairs for the test article and IS were used toselectively measure the test articles. Papp (apparent permeabilityexpressed in nm/sec [nanometer/second]) values were calculated accordingto the following equation:

${{Papp}\left( {{nm}\text{/}\sec} \right)} = {\left( \frac{dQ}{dt} \right) \times \left( \frac{1}{C\; 0} \right) \times \left( \frac{1}{A} \right)}$

Where dQ/dt is the permeability rate, C₀ is the initial concentration inthe donor solution (expressed as IS ratio), A and B are the surfaceareas of the filter (the surface area of the cell monolayer).

Monolayer efflux ratios (ER) were derived using the following equation:

${EffluxRatio} = {\left( \frac{B - {{APapp}\left( {{nm}\text{/}\sec} \right)}}{A - {{BPapp}\left( {{nm}\text{/}\sec} \right)}} \right).}$

Compounds with a MDCKII-MDR1 efflux ratio of less than or equal to 2.5are likely to demonstrate ability to cross the blood-brain-barrier.

Metabolic Stability (Hepatocytes)

The metabolic stability of compounds was evaluated in humancryopreserved hepatocytes (BioreclamationIVT, NY, USA) in duplicate.Test articles (or controls) were added to a 24-well incubation plate(Becton Dickinson Labware, USA) containing 0.5×10⁶ hepatocytes/mL insuspension. The plate was held at 37° C. and agitated with constantorbital shaking (orbital speed at 350 rpm). At each time point (0, 5,10, 15, 20, 30, 45, 60, 90, 120, 150 and 180 min) a Tecan Evo robotaspirated 50 μL of the incubation mixture and 100 μL of acetonitrilecontaining internal standard to quench the reaction. The quenchedmixtures were dispensed into a 96-well plate along with 120 μL ofaqueous solution to equilibrate the solvent content at 37%. Samples werecentrifuged (3000 rpm for 10 minutes) and the plate sealed prior toinjection onto an LC-MS/MS system.

The appropriate parent/daughter ions were monitored for the test articleand IS with the LC-MS/MS system. The intrinsic clearance (Cl_(int);expressed μL/min/million cells) was determined from the first orderelimination constant (k, min⁻¹) of test article decay and the volume ofthe incubation. These values were scaled to intrinsic organ clearance(CL_(int)) using human specific scaling factors (139×10⁶ hepatocytes/gliver and 25.7 g liver/kg body weight). The intrinsic organ CL was thenconverted to the hepatic clearance (CL_(hep)) using the well-stirredmodel as shown below, where Q_(h) is human hepatic blood flow.

${CL}_{hep} = \frac{Q_{h}*{CL}_{int}}{\left( {Q_{h} + {CL}_{int}} \right)}$

Hepatic clearance is expressed as mL/min/kg. The hepatic clearancerelates to the flow of blood through the liver that is completelycleared of the compound. A human CL_(hep) of 20.9 mL/min/kg correspondsto approximately complete compound clearance by the liver or 100% ofliver blood flow. Accordingly, a human CL_(hep) of 6 mL/min/kgcorresponds to a clearance of approximately 29% of liver blood flow. Ahuman CL_(hep) value of 2 mL/min/kg corresponds to a clearance ofapproximately 10% of liver blood flow. A human CL_(hep) value of 1mL/min/kg or less corresponds to a clearance of approximately 5% ofliver blood flow or less. A human CL_(hep) value of 0 mL/min/kgcorresponds to undetectable compound clearance by the liver.

In certain embodiments provided are compounds having a CL_(hep) of lessthan 5, 4, 3, 2, or 1 mL/min/kg when tested according to the above humanhepatic stability assay. In certain embodiments such compounds do notreadily cross the blood brain barrier. In certain embodiments suchcompounds have a MDCKII-MDR1 efflux ratio of greater than 2.5.

In certain embodiments provided are compounds having a CL_(hep) of lessthan 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 mL/min/kg when tested according tothe above human hepatic stability assay. In certain embodiments suchcompounds are able to cross the blood brain barrier. In certainembodiments such compounds have a MDCKII-MDR1 efflux ratio of 2.5 orless.

Protein Binding

The protein binding in plasma was determined using a Rapid EquilibriumDialysis Device (Thermo Scientific RED Device) or 96-well dialyzerapparatus (HTDialysis LLC). Plasma was spiked with test/controlcompounds to give a final concentration of 0.5 μM (plasma). If required,plasma samples were pre-incubated (2 hours at 37° C.) with diisopropylfluorophosphate (DFP) at the final concentration of 100 μM to preventcompound degradation due to amide hydrolysis. Appropriate volumes ofspiked samples along with blank phosphate buffer were added to eitherdevice and incubated at 37° C. for a total of 5 hours with agitation at500 rpm. Following incubation, an equal aliquot of dialysed matrix(plasma or buffer) is added to an equal volume of the opposite blankmatrix such that the volume of buffer to plasma are equal. Mixed matrixsamples were extracted by protein precipitation using acetonitrilecontaining the appropriate IS. Samples were then centrifuged for 10 minat 2800 rpm. Supernatants were collected and diluted and then injectedon to an HPLC-MS/MS or UPLC-MS/MS system. Samples were analyzed bymonitoring the appropriate parent/daughter ion transitions for the testand control compounds. The peak area ratios were used to measure testitem concentrations. The fraction unbound (Afu) was determined as theratio of the peak area ratio in buffer divided by the peak area ratio inplasma.

In Vivo Pharmacokinetic (PK) Studies

The PK properties of test articles were determined in maleSprague-Dawley Crl:CD(SD) rats, male Beagle dogs and male cynomolgusmonkeys. Studies were conducted to the highest standards of animalwelfare in accordance with national legislation and under approval ofthe internal animal care and use committees.

Compounds were administered by IV bolus to animals following anovernight fast. Compounds for IV administration were formulated assolutions using either 1% DMSO (dimethyl sulfoxide):20% PEG400(polyethylene glycol 400):79% saline, or 5-50% NMP in D5W (5% dextrosein water). The formulations were administered at dose volumes rangingfrom 0.5-2 mL/kg. The IV dose ranged from 0.5-1 mg/kg.

Following dose administration, 8-9 serial blood samples were collectedover 24 hours. Samples were mixed with anticoagulant and placed on wetice prior to processing. Plasma was harvested following centrifugation,extracted using protein precipitation with acetonitrile containing IS.The processed supernatant was analyzed using UPLC or LC-MS/MS usingspecific parent/daughter ion pairs for the test article and IS. Plasmaconcentrations were determined using a calibration curve prepared usingknown concentrations of analyte. Pharmacokinetic parameters utilizingmeasured concentrations were calculated using Phoenix WinNonlin. Theunbound plasma clearance was calculated as the ratio of the total bodyclearance divided by the fraction unbound in plasma.

Unless otherwise defined, all technical and scientific terms used hereinhave the same meaning as commonly understood by one of ordinary skill inthe art to which this invention belongs.

The inventions illustratively described herein may suitably be practicedin the absence of any element or elements, limitation or limitations,not specifically disclosed herein. Thus, for example, the terms“comprising”, “including,” “containing”, etc. shall be read expansivelyand without limitation. Additionally, the terms and expressions employedherein have been used as terms of description and not of limitation, andthere is no intention in the use of such terms and expressions ofexcluding any equivalents of the features shown and described orportions thereof, but it is recognized that various modifications arepossible within the scope of the invention claimed.

All publications, patent applications, patents, and other referencesmentioned herein are expressly incorporated by reference in theirentirety, to the same extent as if each were incorporated by referenceindividually. In case of conflict, the present specification, includingdefinitions, will control.

It is to be understood that while the disclosure has been described inconjunction with the above embodiments, that the foregoing descriptionand examples are intended to illustrate and not limit the scope of thedisclosure. Other aspects, advantages and modifications within the scopeof the disclosure will be apparent to those skilled in the art to whichthe disclosure pertains.

1. A compound of Formula I:

wherein R¹ is H or optionally substituted C₁-C₆ alkyl; X¹ and X²together form an optionally substituted aryl of formula:

Y¹ is NR², where R² and R¹ together with the nitrogen atoms to whichthey are attached, form an optionally substituted heterocyclyl oroptionally substituted heteroaryl ring; Y² is —O— or —C(R⁶)₂—; each R⁶is independently H, halo, optionally substituted C₁-C₆ alkyl, or two R⁶together with the carbon atom to which they are attached, form a C₁-C₆alken-1-yl, optionally substituted cycloalkyl or optionally substitutedheterocyclyl ring; R³ and R⁴ are independently H, halo, optionallysubstituted C₁-C₆ alkyl, R³ and R⁴ together with the carbon atoms towhich they are attached, form an optionally substituted cycloalkyl oroptionally substituted heterocyclyl ring, or R³ and R⁶ together with thecarbon atoms to which they are attached, form an optionally substitutedcycloalkyl or optionally substituted heterocyclyl ring; A is anoptionally substituted cycloalkyl, optionally substituted heterocyclylring or optionally substituted heteroaryl ring; L is absent, —O—, —S—,—S(O)—, —S(O)₂—, —NR⁷— or —C(R⁸)₂—; R⁷ is H or optionally substitutedC₁-C₆ alkyl; each R⁸ is independently H, halo, optionally substitutedC₁-C₆ alkyl, or two R⁸ together with the carbon atom to which they areattached, form a optionally substituted cycloalkyl or optionallysubstituted heterocyclyl ring; and R⁹ is optionally substitutedcycloalkyl, optionally substituted heterocyclyl, optionally substitutedaryl or optionally substituted heteroaryl; provided that at least one ofthe following occurs: (1) at least one of R³ and R⁴ are halo oroptionally substituted C₁-C₆ alkyl, R³ and R⁴ together with the carbonatoms to which they are attached, form an optionally substitutedcycloalkyl or optionally substituted heterocyclyl ring, or R³ and R⁶together with the carbon atoms to which they are attached, form aoptionally substituted cycloalkyl or optionally substituted heterocyclylring; (2) L is absent or —C(R⁸)₂—, and each R⁸ is optionally substitutedC₁-C₆ alkyl or halo provided that the compound is not5-(difluoro(phenyl)methyl)-N-(4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)isoxazole-3-carboxamideor not5-(difluoro(phenyl)methyl)-N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)isoxazole-3-carboxamideor two R⁸ together with the carbon atom to which they are attached, forman optionally substituted cycloalkyl or optionally substitutedheterocyclyl ring; (3) Y is NR²; (4) Y² is —C(R⁶)₂—; and one R⁶ ishydrogen, halo, or optionally substituted C₁-C₆alkyl, and the other R⁶is halo or optionally substituted C₁-C₆ alkyl; or two R⁶ together withthe carbon atom to which they are attached, form a C₁-C₆ alken-1-yl,optionally substituted cycloalkyl or optionally substituted heterocyclylring; (5) Y² is —O—; and A is substituted with halo or cyano; or A isthiazolyl or a 3- or 4-membered ring; provided that the compound is not2-(4-bromobenzyl)-N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)thiazole-4-carboxamideor2-benzyl-N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)thiazole-4-carboxamide;(6) the carbonyl moiety and L are substituted other than 1,3- on ring A;or a pharmaceutically acceptable salt, prodrug, tautomer, stereoisomeror mixture of stereoisomers thereof.
 2. (canceled)
 3. The compound ofclaim 1, wherein the moiety:

is

wherein X⁶, X⁷, X⁸ and X⁹ are each N or CH; q is 0, 1 or 2; each R¹⁰ isindependently cyano, halo, optionally substituted C₁-C₆ alkyl or—S(O)₂—C₁-C₆ alkyl. 4-20. (canceled)
 21. The compound of claim 3,wherein each R¹⁰ is independently cyano, halo or optionally substitutedalkyl.
 22. The compound of claim 3, wherein X⁶, X⁷, X⁸ and X⁹ are eachCH.
 23. The compound of claim 1, wherein Y² is O.
 24. The compound ofclaim 1, wherein R³ is hydrogen or fluoro.
 25. The compound of claim 1,wherein both R³ and R⁴ are fluoro, or either R³ or R⁴ are fluoro and theother is hydrogen, or R³ and R⁴ form a cyclopropyl or R³ joins with R⁶to form a cyclopropyl.
 26. The compound of claim 1, wherein A is phenyl,phenylbenzo[d]thiazolyl, isoxazolyl, oxazolyl, pyrazolyl, triazolyl,5,6-dihydro-4H-pyrrolo[1,2-b]pyrazolyl, pyrrolyl, thiazolyl, imidazolyl,thiadiazolyl, cyclobutyl, cyclopropyl, or azetidinyl.
 27. The compoundof claim 1, wherein L is absent, —S(O)₂— or —C(R⁸)₂—.
 28. The compoundof claim 1, wherein two R⁸ together with the carbon atom to which theyare attached, form an optionally substituted cycloalkyl or optionallysubstituted heterocyclyl ring.
 29. The compound of claim 1, wherein R⁹is optionally substituted pyridyl, phenyl or 2,3-dihydro-1H-indenyl. 29.The compound of claim 1, wherein the compound is of Formula IVa, IVb,IVc, IVd, IVe, IVf or IVg:

or a pharmaceutically acceptable salt, prodrug, tautomer, stereoisomeror mixture of stereoisomers thereof; wherein q is 0, 1 or 2; R⁴ is H,halo, or optionally substituted C₁-C₆ alkyl; A is an optionallysubstituted cycloalkyl, optionally substituted heterocyclyl, optionallysubstituted aryl or optionally substituted heteroaryl ring; L is absent,—O—, —S—, —S(O)—, —S(O)₂—, —NR⁷— or —C(R⁸)₂—; R⁷ is H or optionallysubstituted C₁-C₆ alkyl; each R⁸ is independently H, halo, or optionallysubstituted C₁-C₆ alkyl, or two R⁸ together with the carbon atom towhich they are attached, form an optionally substituted cycloalkyl oroptionally substituted heterocyclyl ring; R⁹ is optionally substitutedcycloalkyl, optionally substituted heterocyclyl, optionally substitutedaryl or optionally substituted heteroaryl; and each R¹⁰ is independentlycyano, halo, optionally substituted C₁-C₆ alkyl, or —S(O)₂—C₁-C₆ alkyl.30. A compound or a pharmaceutically acceptable salt, prodrug, tautomer,stereoisomer or mixture of stereoisomers thereof that is:


31. A pharmaceutical composition comprising a compound from claim 1 andan excipient.
 32. A pharmaceutical composition comprising a compoundfrom claim 30 and an excipient.
 33. A method of treating areceptor-interacting protein kinase 1-mediated disease or disorder in asubject in need thereof comprising administering a therapeuticallyeffective amount of the compound according to claim 1 to the subject inneed thereof, wherein the receptor-interacting protein kinase 1-mediateddisease or disorder is an inflammatory disease or disorder, a necroticcell disease, a neurodegenerative disease, a central nervous systemdisease, an ocular disease, a malignancy, an immune-mediated disease, anallergic disease, an autoimmune disease, inflammatory bowel disease,Crohn's disease, ulcerative colitis, psoriasis, retinal detachment,retinitis pigmentosa, macular degeneration, pancreatitis, atopicdermatitis, rheumatoid arthritis, spondyloarthritis, gout, SoJIA,systemic lupus erythematosus, Sjogren's syndrome, systemic scleroderma,anti-phospholipid syndrome, vasculitis, osteoarthritis, non-alcoholsteatohepatitis, alcohol steatohepatitis, autoimmune hepatitis,autoimmune hepatobiliary diseases, primary sclerosing cholangitis,nephritis, Celiac disease, autoimmune ITP, transplant rejection,ischemia reperfusion injury of solid organs, sepsis, systemicinflammatory response syndrome, cerebrovascular accident, myocardial orcardiac infarction, Huntington's disease, Alzheimer's disease,Parkinson's disease, asthma, multiple sclerosis, type I diabetes,Wegener's granulomatosis, pulmonary sarcoidosis, Behget's disease,interleukin-1 converting enzyme associated fever syndrome, chronicobstructive pulmonary disease, tumor necrosis factor receptor-associatedperiodic syndrome, periodontitis, trauma, ischemia, stroke, infection,lysosomal storage disease, Gaucher's disease, Krabbe disease,Niemann-Pick disease, amyotrophic lateral sclerosis (ALS/Lou Gehrig'sDisease), HIV-associated dementia, retinal degenerative disease,glaucoma, age-related macular degeneration, psoriasis, psoriaticarthritis, brain injury, spinal cord injury, dementia, diabeticneuropathy, polyglutamine (polyQ) disease, Fahr disease, Menke'sdisease, Wilson's disease, cerebral ischemia, Friedrich's ataxia,rheumatoid arthritis, Lewy body disease, or a prion disorder.